Bicyclic and tricyclic amines as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (I): 
 
A-E-NR 1 -G  (I) 
or pharmaceutically acceptable salt forms thereof, useful for the prevention of inflammatory diseases such as asthma and other allergic diseases.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases such as asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J. Med., 338,436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are twomajor classes of chemokines, CXC and CC, depending on whether the firsttwo cysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and-3) are chemotactic for, among other cell types, macrophages, Tlymphocytes, eosinophils, dendritic cells, and basophils. There alsoexist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines),and fractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[I-309, TARC, MIP-1β] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, the chemokine receptor CCR-3 plays a pivotal role in attractingeosinophils to sites of allergic inflammation and in subsequentlyactivating these cells. The chemokine ligands for CCR-3 induce a rapidincrease in intracellular calcium concentration, increased expression ofcellular adhesion molecules, cellular degranulation, and the promotionof eosinophil migration. Accordingly, agents which modulate chemokinereceptors would be useful in such disorders and diseases. In addition,agents which modulate chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

A substantial body of art has accumulated over the past several decadeswith respect to substituted piperidines and pyrrolidines. Thesecompounds have implicated in the treatment of a variety of disorders.

WO 98/25604 describes spiro-substituted azacycles which are useful asmodulators of chemokine receptors:

wherein R₁ is C₁₋₆ alkyl, optionally substituted with functional groupssuch as —NR⁶CONHR⁷, wherein R⁶ and R⁷ may be phenyl further substitutedwith hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds arenot considered part of the present invention.

WO 95/13069 is directed to certain piperidine, pyrrolidine, andhexahydro-1H-azepine compounds of general formula:

wherein A may be substituted alkyl or Z-substituted alkyl, withZ=NR_(6a) or O. Compounds of this type are claimed to promote therelease of growth hormone in humans and animals.

WO 93/06108 discloses pyrrolobenzoxazine derivatives as5-hydroxytryptamine (5-HT) agonists and antagonists:

wherein A is lower alkylene and R⁴ may be phenyl optionally substitutedwith halogen.

U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonistscomprising 1,4-dihydropyridines with a piperidinyl ortetrahydropyridinyl-containing moiety attached to the 3-position of the4-phenyl ring:

wherein B may be NH, NR¹, O, or a bond, and R⁷ may be substitutedphenyl, benzyl, phenethyl and the like.

These reference compounds are readily distinguished structurally byeither the nature of the urea functionality, the attachment chain, orthe possible substitution of the present invention. The prior art doesnot disclose nor suggest the unique combination of structural fragmentswhich embody these novel piperidines and pyrrolidines as having activitytoward the chemokine receptors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelagonists or antagonists of CCR-3, or pharmaceutically acceptable saltsor prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating inflammatory and allergic disorders comprising administering toa host in need of such treatment a therapeutically effective amount ofat least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):A-E-NR¹-G  (I)or stereoisomers or pharmaceutically acceptable salts thereof, whereinA, E, G and R¹ are defined below, are effective modulators of chemokineactivity.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Thus, in a first embodiment, the present invention provides novelcompounds of formula (I):A-E-NR¹-G  (I)or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

-   A is selected from-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),-   ring D is selected from a C₃₋₆ carbocyclic residue and a 5 or 6    membered heterocycle;-   G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³,    —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,    C(═C(CN)₂)NR²R³,-   W, at each occurrence, is independently selected from C or N,    provided at least two of W are C;-   X¹ and X² are independently selected from C and N;-   Z¹ is selected from C and N;-   Z² is selected from NR^(1′), O, S and C;-   R¹, R^(1′) and R² are independently selected from H, C₁₋₈ alkyl,    C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a);-   R^(1a) is independently selected from H, C₁₋₆ alkyl, —OH, —CN, —NO₂,    (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(a);-   R^(a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CHR′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CHR′)_(r)NR^(b)R^(b), (CHR′)_(r)OH,    (CHR′)_(r)OR^(c), (CHR′)_(r)SH, (CHR′)_(r)SR^(c),    (CHR′)_(r)C(O)R^(b), (CHR′)_(r)C(O)NR^(b)R^(b),    (CHR′)_(r)NR^(b)C(O)R^(b), (CHR′)_(r)C(O)OR^(b),    (CHR′)_(r)OC(O)R^(c), (CHR′)_(r)CH(═NR^(b))NR^(b)R^(b),    (CHR′)_(r)NHC(═NR^(b))NR^(b)R^(b), (CHR′)_(r)S(O)_(p)R^(c),    (CHR′)_(r)S(O)₂NR^(b)R^(b), (CHR′)_(r)NR^(b)S(O)₂R^(c), and    (CHR′)_(r)phenyl;-   R^(b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   alternatively, R¹ and R² join to form a 5, 6, or 7-membered ring    substituted with 0-3 R^(a);-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R¹⁵ and a (CR^(3′)R^(3″))_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈    alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),    (CH₂)_(q)C(O)NR^(4a)R^(4a′), (CH₂)_(q)C(O)OR^(4a), and a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c);-   R^(4a) and R^(4a′), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;-   R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4a)R^(4a′), and (CH₂)_(r)phenyl;-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(q)OH, (CHR′)_(q)SH, (CHR′)_(q)OR^(7d), (CHR′)_(q)SR^(7d),    (CH₂CHR′)_(q)NR^(7a)R^(7a′), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(7b),    (CHR′)_(r)C(O)NR^(7a)R^(7a′), (CHR′)_(q)NR^(7a)C(O)R^(7b),    (CHR′)_(q)NR^(7a)C(O)H, (CHR′)_(r)C(O)OR^(7a),    (CHR′)_(q)OC(O)R^(7b), (CHR′)_(q)S(O)_(p)R^(7b),    (CHR′)_(q)S(O)₂NR^(7a)R^(7a′), (CHR′)_(q)NR^(7a)S(O)₂R^(7b),    (CHR′)_(q)NHC(O)NR^(7a)R^(7a′), (CHR′)_(q)NHC(O)OR^(7a),    (CHR′)_(q)OC(O)NR^(7a)R^(7a′), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c), and a    (CHR′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);-   R^(7a) and R^(7a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),    (CH₂)_(r)NR^(7f)C(O)R^(7b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f),    (CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-3 R^(7e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(8a);-   R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, ═NR^(8b), or    ═O;-   R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and    (CH₂)_(r)-phenyl;-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CHR′)_(r)OH, (CHR′)_(r)SH, (CHR′)_(r)OR^(9d),    (CHR′)_(r)SR^(9d), (CHR′)_(r)NR^(9a)R^(9a′), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)R^(9b), (CHR′)_(r)C(O)NR^(9a)R^(9a′),    (CHR′)_(r)NR^(9a)C(O)R^(9b), (CHR′)_(r)NR^(9a)C(O)H,    (CHR′)_(r)NR^(9a)C(O)NR^(9a)R^(9a), (CHR′)_(r)C(O)OR^(9a),    (CHR′)_(r)OC(O)R^(9b), (CHR′)_(r)S(O)_(p)R^(9b),    (CHR′)_(r)S(O)₂NR^(9a)R^(9a′), (CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆    haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(9c), and a (CHR′)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(9c);-   R^(9a) and R^(9a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(9e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9f)R^(9f),    (CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)_(p)R^(9b), (CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)₂NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)S(O)₂R^(9b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(9e);-   R^(9d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-3 R^(9e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(9c), and a 5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from the    group consisting of N, O, and S substituted with 0-3 R^(9c);-   R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   R^(9f) at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d),    (CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a′), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a′),    (CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,    (CH₂)_(r)C(O)OR^(10a), (CH₂)_(r)OC(O)R^(10b),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a′),    (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(10c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);-   R^(10a) and R^(10a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(10e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),    (CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(10e);-   R^(10d), at each occurrence, is selected from methyl, CF₃, C₂₋₆    alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, a    C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c), and a 5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from the group consisting of N, O, and S substituted with 0-3    R^(10c); R^(10e), at each occurrence, is selected from C₁₋₆ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-membered    cyclic ketal, or ═O;-   with the proviso that when R¹⁰ is —OH, R⁹ is not halogen, cyano, or    bonded to the carbon to which it is attached through a heteroatom;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),    (CH₂)_(q)NR^(11a)R^(11a′), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),    (CH₂)_(r)C(O)NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)C(O)R^(11b),    (CH₂)_(q)NR^(11a)C(O)NR^(11a)R^(11a), (CH₂)_(r)C(O)OR^(11a),    (CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),    (CH₂)_(q)S(O)₂NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(11c);-   R^(11a) and R^(11a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),    (CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),    (CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),    (CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is selected from methyl, CF₃, C₂₋₆    alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and    a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(11c);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆    cycloalkyl, and (CH₂)_(t)phenyl substituted with 0-3 R^(12a);-   R^(12a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;-   R¹⁴ is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, C(O)NR^(14a)R^(14a′), C(O)R^(14b),    C(O)OC₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)R^(14b), (CH₂)_(r)phenyl    substituted with 0-3 R^(14c), OR^(14a), NR^(14a)R^(14a′), ═O, and    NR^(14a)C(O)R^(14a′);-   R^(14a) and R^(14a′), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted    with 0-3 R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(14c);-   R^(14b), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(14c); and-   R^(14c), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,    (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(w)phenyl;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(15a)R^(15a′),    (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH,    (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a′),    (CHR′)_(r)NHC(═NR^(15f))NR^(15a)R^(15a′),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl    substituted with R^(15e);-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   R^(15d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈    alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(15e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e),    and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e);-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl;-   R^(15f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,    (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a′),    (CHR′)_(r)NHC(═NR^(16f))NR^(16a)R^(16a′),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue    substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈    alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(16e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(16e);-   R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl;-   R^(16f), at each occurrence, is selected from H, C₁₋₅ alkyl, and    C₃₋₆ cycloalkyl, and phenyl;-   R¹⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(r)OH, (CHR′)_(r)SH, (CHR′)_(r)OR^(17d), (CHR′)_(r)SR^(17d),    (CHR′)_(r)NR^(17a)R^(17a′), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(17b),    (CHR′)_(r)C(O)NR^(17a)R^(17a′), (CHR′)_(r)NR^(17a)C(O)R^(17b),    (CHR′)_(r)NR^(17a)C(O)H, (CHR′)_(r)C(O)OR^(17a),    (CHR′)_(r)OC(O)R^(17b), (CHR′)_(r)S(O)_(p)R^(17b),    (CHR′)_(r)S(O)₂NR^(17a)R^(17a′), (CHR′)_(r)NR^(17a)S(O)₂R^(17b),    C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(17c), and a (CHR′)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(17c);-   R^(17a) and R^(17a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(17e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(17e);-   R^(17b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(17e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(17e);-   R^(17c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(17f)R^(17f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(17b), (CH₂)_(r)C(O)NR^(17f)R^(17f),    (CH₂)_(r)NR^(17f)C(O)R^(17a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(17b), (CH₂)_(r)C(═NR^(17f))NR^(17f)R^(17f),    (CH₂)_(r)S(O)_(p)R^(17b), (CH₂)_(r)NHC(═NR^(17f))NR^(17f)R^(17f),    (CH₂)_(r)S(O)₂NR^(17f)R^(17f), (CH₂)_(r)NR^(17f)S(O)₂R^(17b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(17e);-   R^(17d), at each occurrence, is selected from methyl, CF₃, C₁₋₆    alkyl substituted with 0-3 R^(17e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and    a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(17c);-   R^(17e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(17f)R^(17f), and (CH₂)_(r)phenyl;-   R^(17f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹⁸, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(q)OH, (CHR′)_(q)SH, (CHR′)_(q)OR^(18d), (CHR′)_(q)SR^(18d),    (CHR′)_(q)NR^(18a)R^(18a′), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(18b),    (CHR′)_(r)C(O)NR^(18a)R^(18a′), (CHR′)_(q)NR^(18a)C(O)R^(18b),    (CHR′)_(q)NR^(18a)C(O)H, (CHR′)_(r)C(O)OR^(18a),    (CHR′)_(q)OC(O)R^(18b), (CHR′)_(q)S(O)_(p)R^(18b),    (CHR′)_(q)S(O)₂NR^(18a)R^(18a′), (CHR′)_(q)NR^(18a)S(O)₂R^(18b),    C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(18c), and a (CHR′)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(18c);-   R^(18a) and R^(18a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(18e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(18e);-   R^(18b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(18e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(18e);-   R^(18c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(18f)R^(18f)f, (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(18b), (CH₂)_(r)C(O)NR^(18f)R^(18f),    (CH₂)_(r)NR^(18f)C(O)R^(18b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(18b), (CH₂)_(r)C(═NR^(18f))NR^(18f)R^(18f))    (CH₂)_(r)S(O)_(p)R^(18b), (CH₂)_(r)NHC(═NR^(18f))NR^(18f)R^(18f),    (CH₂)_(r)S(O)₂NR^(18f)R^(18f), (CH₂)_(r)NR^(18f)S(O)₂R^(18b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(18e);-   R^(18d), at each occurrence, is selected from methyl, CF₃, C₁₋₆    alkyl substituted with 0-3 R^(18e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and    a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(18c);-   R^(18e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(18f)R^(18f), and (CH₂)_(r)phenyl;-   R^(18f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   a is selected from 0 and 1;-   b is selected from 0 and 1, wherein if a=0, then b=1;-   c is selected from 0, 1, and 2;-   d is selected from 0, 1, and 2, wherein c+d equals 1 or 2;-   provided that if b=1, c=1, and d=1 then E cannot be    —(CR⁷R⁸)—(CR⁹CR¹⁰)_(v)—(CR¹¹CR¹²)—;-   e is selected from 0 and 1;-   f is selected from 0 and 1, wherein e+f equals 1 or 2;-   g is selected from 0, 1, 2 and 3;-   h is selected from 0 and 1;-   i is selected from 1, 2, 3, 4, and 5;-   j is selected from 0, 1, 2, 3, 4, and 5;-   k is selected from 0, 1, and 2;-   l is selected from 0, 1, 2 and 3, wherein l+h equals 2 or 3;-   v, at each occurrence, is independently selected from 0, 1, and 2;-   t, at each occurrence, is selected from 1 and 2;-   w, at each occurrence, is selected from 0 and 1;-   r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;-   s, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;-   q, at each occurrence, is selected from 1, 2, 3, 4, and 5; and-   p, at each occurrence, is selected from 1 and 2.

In another embodiment, the present invention provides novel compounds offormula (1), wherein:

-   R⁴ is absent or, taken with the nitrogen to which it is attached to    form an N-oxide;-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(q)OH, (CHR′)_(q)OR^(7d), (CHR′)_(q)NR^(7a)R^(7a′),    (CHR′)_(r)C(O)R^(7b), (CHR′)_(r)C(O)NR^(7a)R^(7a′),    (CHR′)_(q)NR^(7a)C(O)R^(7b), (CHR′)_(q)NR^(7a)C(O)H,    (CHR′)_(q)S(O)₂NR^(7a)R^(7a′), (CHR′)_(q)NR^(7a)S(O)₂R^(7b),    (CHR′)_(q)NHC(O)NHR^(7a), (CHR′)_(q)NHC(O)OR^(7a),    (CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c), and a    (CHR′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);-   alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, ═NR^(8b), or    ═O;-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CHR′)_(r)OH, (CHR′)_(r)OR^(9d), (CHR′)_(r)NR^(9a)R^(9a′),    (CHR′)_(r)C(O)R^(9b), (CHR′)_(r)C(O)NR^(9a)R^(9a′),    (CHR′)_(r)NR^(9a)C(O)R^(9b), (CHR′)_(r)NR^(9a)C(O)H,    (CHR′)_(r)NR^(9a)C(O)NHR^(9a), (CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆    haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(9c), and a (CHR′)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(9c);-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a′),    (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a′),    (CH₂)_(q)NR^(11a)C(O)R^(11a), (CH₂)_(q)NR^(11a)C(O)NHR^(11a),    (CH₂)_(q)NHC(O)NHR^(7a), (CH₂)_(q)NHC(O)OR^(7a),    (CH₂)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(11c), and a    (CH₂′)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c).

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³,    —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, and    C(═C(CN)₂)NR²R³.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹⁷ is selected from H;-   R¹⁸ is selected from H;-   j is selected from 0, 1, and 2;-   i is selected from 1 and 2;-   s is selected from 0, 1, and 2; and-   g is selected from 0, 1, and 2.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹ is selected from H;-   R² is selected from H; and-   G is selected from —C(O)NR²R³, C(═CHCN)NR²R³, C(—CHNO₂)NR²R³, and    C(═C(CN)₂)NR²R³.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R⁷ is selected from H;-   R⁸ is selected from H; and-   R¹² is selected from H.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵ and a (CR^(3′)CR^(3″))_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, subtituted with 0-3 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    CN, (CF₂)_(r)CF₃, and OH.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   E is

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   E is-   ring D is selected from a C₃₋₆ carbocyclic residue;-   R⁷ is selected from H; and-   R⁸ is selected from H.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵ and a (CR^(3′)CR^(3″))_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, subtituted with 0-3 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   G is selected from

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹ is selected from H;-   both X¹ and X² cannot be C; and-   Z² is selected from NR^(1′), O, and S.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   R¹⁷ is selected from H;-   R¹⁸ is selected from H;-   j is selected from 0, 1, and 2;-   i is selected from 1 and 2;-   s is selected from 0, 1, and 2; and-   g is selected from 0, 1, and 2.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R⁷ is selected from H;-   R⁸ is selected from H; and-   R¹² is selected from H.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e); R^(16e), at each occurrence, is selected from    methyl, ethyl, Cl, F, Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In another embodiment, the present invention provides novel compounds offormula (I), wherein:

-   E is

In a further embodimnet, the present invention provides novel compoundsof formula (I), wherein:

-   E is-   ring D is selected from a C₃₋₆ carbocyclic residue;-   R⁷ is selected from H;-   R⁸ is selected from H.

In a further embodiment, the present invention provides novel compoundsof formula (D, wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein:

-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    CN, (CF₂)_(r)CF₃, and OH.

In a further embodiment, the present invention provides novel compoundsof formula (I), wherein the compound of formula I is selected from:

-   N-3-[cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   N-3-[trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea;-   (+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea;-   N-(3-acetylphenyl)-NA-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(4-fluorophenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(3-acetylphenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;    and-   N-(3-acetylphenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea.

In a third embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present invention.

In a fourth embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of thecompounds of the present invention.

In another embodiment, the present invention provides a method fortreating or preventing inflammatory diseases, comprising administeringto a patient in need thereof a therapeutically effective amount of thecompounds of the present invention.

In another embodiment, the present invention provides a method fortreating or preventing asthma, comprising administering to a patient inneed thereof a therapeutically effective amount of the compounds of thepresent invention.

In another embodiment, the present invention provides a method fortreating or preventing asthma, comprising administering to a patient inneed thereof a therapeutically effective amount of compounds of thepresent invention.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I):A-E-NR¹-G  (I)or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

-   ring A is selected from-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),-   ring D is selected from a C₃₋₆ carbocyclic residue and a 5 or 6    membered heterocycle;-   G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³,    —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,    C(═C(CN)₂)NR²R³,-   W, at each occurrence, is independently selected from C or N,    provided at least two of W are C;-   X¹ and X² are independently selected from C and N;-   Z¹ is selected from C and N;-   Z² is selected from NR^(1′), O, S and C;-   R¹, R^(1′) and R² are independently selected from H, C₁₋₈ alkyl,    C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a);-   R^(1a) is independently selected from H, C₁₋₆ alkyl, —OH, —CN, —NO₂,    (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(a);-   R^(a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(b)R^(b), (CH₂)_(r)OH,    (CH₂)_(r)OR^(c), (CH₂)_(r)SH, (CH₂)_(r)SR^(c), (CH₂)_(r)C(O)R^(b),    (CH₂)_(r)C(O)NR^(b)R^(b), (CH₂)_(r)NR^(b)C(O)R^(b),    (CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(c),    (CH₂)_(r)CH(═NR^(b))NR^(b)R^(b), (CH₂)_(r)NHC(═NR^(b))NR^(b)R^(b),    (CH₂)_(r)S(O)_(p)R^(c), (CH₂)_(r)S(O)₂NR^(b)R^(b),    (CH₂)_(r)NR^(b)S(O)₂R^(c), and (CH₂)_(r)phenyl;-   R^(b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   alternatively, R¹ and R² join to form a 5, 6, or 7-membered ring    substituted with 0-3 R^(a);-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R¹⁵ and a (CR^(3′)R^(3″))_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R⁴ is absent, taken with the nitrogen to which it is attached to    form an N-oxide, or selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈    alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),    (CH₂)_(q)C(O)NR^(4a)R^(4a′), (CH₂)_(q)C(O)OR^(4a), and a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c);-   R^(4a) and R^(4a′), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;-   R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;-   R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4a)R^(4a′), and (CH₂)_(r)phenyl;-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7d), (CH₂)_(q)SR^(7d),    (CH₂)_(q)NR^(7a)R^(7a′), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),    (CH₂)_(r)C(O)NR^(7a)R^(7a′), (CH₂)_(q)NR^(7a)C(O)R^(7b),    (CH₂)_(q)NR^(7a)C(O)H, (CH₂)_(r)C(O)OR^(7a), (CH₂)_(q)OC(O)R^(7b),    (CH₂)_(q)S(O)_(p)R^(7b), (CH₂)_(q)S(O)₂NR^(7a)R^(7a′),    (CH₂)_(q)NR^(7a)S(O)₂R^(7b), (CH₂)_(q)NHC(O)N^(7a)R^(7a),    (CH₂)_(q)NHC(O)OR^(7a), (CH₂)_(q)OC(O)N^(7a)R^(7a), C₁₋₆ haloalkyl,    a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c),    and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);-   R^(7a) and R^(7a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7f)R^(7f),    (CH₂)_(r)NR^(7f)C(O)R^(7b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(7b), (CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f))    (CH₂)_(r)S(O)_(p)R^(7b), (CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CH₂)_(r)S(O)₂NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)S(O)₂R^(7b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl    substituted with 0-3 R^(7e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(8a);-   R^(8a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, ═NR^(8b), or    ═O;-   R^(8b) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and    (CH₂)_(r)-phenyl;-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(9d),    (CH₂)_(r)SR^(9d), (CH₂)_(r)NR^(9a)R^(9a′), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a′),    (CH₂)_(r)NR^(9a)C(O)R^(9a), (CH₂)_(r)NR^(9a)C(O)H,    (CH₂)_(r)NR^(9a)C(O)N^(9a)R^(9a), (CH₂)_(r)C(O)OR^(9a),    (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)S(O)_(p)R^(9b),    (CH₂)_(r)S(O)₂NR^(9a)R^(9a′), (CH₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(9c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(9c);-   R^(9a) and R^(9a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(9e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9f)R^(9f),    (CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)_(p)R^(9b), (CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),    (CH₂)_(r)S(O)₂NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)S(O)₂R^(9b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(9e);-   R^(9d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl    substituted with 0-3 R^(9e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(9c), and a 5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from the    group consisting of N, O, and S substituted with 0-3 R^(9c);-   R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   R^(9f) at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,    Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d),    (CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a′), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a′),    (CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,    (CH₂)_(r)C(O)OR^(10a), (CH₂)_(r)OC(O)R^(10b),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a′),    (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(10c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);-   R^(10a) and R^(10a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(10e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F.    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R^(10f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),    (CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),    (CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(10e);-   R^(10d), at each occurrence, is selected from methyl, CF₃, C₁₋₆    alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, a    C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10c), and a 5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from the group consisting of N, O, and S substituted with 0-3    R^(10c);-   R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   alternatively, R⁹ and R¹⁰ join to form C₃₋₇ cycloalkyl, 5-6-membered    cyclic ketal, or ═O;-   with the proviso that when R¹⁰ is —OH, R⁹ is not halogen, cyano, or    bonded to the carbon to which it is attached through a heteroatom;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d),    (CH₂)_(q)NR^(11a)R^(11a′), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b),    (CH₂)_(r)C(O)NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)C(O)R^(11b),    (CH₂)_(q)NR^(11a)C(O)NR^(11a)R^(11a), (CH₂)_(r)C(O)OR^(11a),    (CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),    (CH₂)_(q)S(O)₂NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(11c);-   R^(11a) and R^(11a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),    (CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),    (CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),    (CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is selected from methyl, CF₃, C₁₋₆    alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and    a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(11c);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆    cycloalkyl, and (CH₂)_(t)phenyl substituted with 0-3 R^(12a);-   R^(12a), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   alternatively, R¹¹ and R¹² join to form C₃₋₇ cycloalkyl;-   R¹⁴ is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, C(O)NR^(14a)R^(14a′), C(O)R^(14b),    C(O)OC₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)R^(14b), (CH₂)_(r)phenyl    substituted with 0-3 R^(14c), OR^(14a), NR^(14a)R^(14a′), ═O, and    NR^(14a)C(O)R^(14a′);-   R^(14a) and R^(14a′), at each occurrence, are selected from H, C₁₋₆    alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted    with 0-3 R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(14c);-   R^(14b), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3    R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(14c); and-   R^(14c), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,    (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(w)phenyl;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(15a)R^(15a′),    (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH,    (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a′),    (CHR′)_(r)NHC(═NR^(15f))NR^(15a)R^(15a′),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl    substituted with R^(15e);-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(15e);-   R^(15d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈    alkynyl, methyl, CF₃, C₁₋₆ alkyl substituted with 0-3 R^(15e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e),    and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e);-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl;-   R^(15f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,    (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)OH,    (CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a′),    (CHR′)_(r)NHC(═NR^(16f))NR^(16a)R^(16a′),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue    substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(16e);-   R^(16d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈    alkynyl, methyl, CF₃, C₁₋₆ alkyl substituted with 0-3 R^(16e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(16e);-   R^(16e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; R^(16f), at    each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R¹⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(17d), (CH₂)_(q)SR^(17d),    (CH₂)_(q)NR^(17a)R^(17a′), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(17b),    (CH₂)_(r)C(O)NR^(17a)R^(17a′), (CH₂)_(q)NR^(17a)C(O)R^(17b),    (CH₂)_(q)NR^(17a)C(O)H, (CH₂)_(r)C(O)OR^(17a),    (CH₂)_(q)OC(O)R^(17b), (CH₂)_(q)S(O)_(p)R^(17b),    (CH₂)_(q)S(O)₂NR^(17a)R^(17a′), (CH₂)_(q)NR^(17a)S(O)₂R^(17b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(17c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(17c);-   R^(17a) and R^(17a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(17e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(17e);-   R^(17b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(17e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(17e);-   R^(17c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(17f)R^(17f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(17b), (CH₂)_(r)C(O)NR^(17f)R^(17f),    (CH₂)_(r)NR^(17f)C(O)R^(17a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(17b), (CH₂)_(r)C(═NR^(17f))NR^(17f)R^(17f),    (CH₂)_(r)S(O)_(p)R^(17b), (CH₂)_(r)NHC(═NR^(17f))NR^(17f)R^(17f),    (CH₂)_(r)S(O)₂NR^(17f)R^(17f), (CH₂)_(r)NR^(17f)S(O)₂R^(17b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(17e);-   R^(17d), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(17e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(17c);-   R^(17e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(17f)R^(17f), and (CH₂)_(r)phenyl;-   R^(17f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹⁸, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(18d), (CH₂)_(q)SR^(18d),    (CH₂)_(q)NR^(18a)R^(18a′), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(18b),    (CH₂)_(r)C(O)NR^(18a)R^(18a′), (CH₂)_(q)NR^(18a)C(O)R^(18b),    (CH₂)_(q)NR^(18a)C(O)H, (CH₂)_(r)C(O)OR^(18a),    (CH₂)_(q)OC(O)R^(18b), (CH₂)_(q)S(O)_(p)R^(18b),    (CH₂)_(q)S(O)₂NR^(18a)R^(18a′), (CH₂)_(q)NR^(18a)S(O)₂R^(18b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(18c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(18c);-   R^(18a) and R^(18a′), at each occurrence, are selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(18e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(18e);-   R^(18b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R^(18e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(18e);-   R^(18c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(18f)R^(18f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(18b), (CH₂)_(r)C(O)NR^(18f)R^(18f),    (CH₂)_(r)NR^(18f)C(O)R^(18b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(18b), (CH₂)_(r)C(═NR^(18f))NR^(18f)R^(18f),    (CH₂)_(r)S(O)_(p)R^(18b), (CH₂)_(r)NHC(═NR^(18f))NR^(18f)R^(18f),    (CH₂)_(r)S(O)₂NR^(18f)R^(18f), (CH₂)_(r)NR^(18f)S(O)₂R^(18b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(18e);-   R^(18d), at each occurrence, is selected from methyl, CF₃, C₁₋₆    alkyl substituted with 0-3 R^(18e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and    a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(18c);-   R^(18e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(18f)R^(18f), and (CH₂)_(r)phenyl;-   R^(18f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   a is selected from 0 and 1;-   b is selected from 0 and 1, wherein if a=0, then b=1;-   c is selected from 0, 1, and 2;-   d is selected from 0, 1, and 2, wherein c+d equals 1 or 2;-   e is selected from 0 and 1;-   f is selected from 0 and 1, wherein e+f equals 1 or 2;-   g is selected from 0, 1, 2 and 3;-   h is selected from 0 and 1;-   i is selected from 0, 1, 2, 3, 4, and 5;-   j is selected from 0, 1, 2, 3, 4, and 5;-   k is selected from 0, 1, and 2;-   l is selected from 0, 1, 2 and 3, wherein l+h equals 2 or 3;-   v, at each occurrence, is independently selected from 0, 1, and 2;-   t is selected from 1 and 2;-   w is selected from 0 and 1;-   r is selected from 0, 1, 2, 3, 4, and 5;-   s is selected from 0, 1, 2, 3, 4, and 5;-   q is selected from 1, 2, 3, 4, and 5; and-   p is selected from 1 and 2.

In another embodiment, the present invention provides method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

In another embodiment, method of modulating chemokine receptor byadministering a compound of formula (I), wherein:

-   R⁴ is absent or, taken with the nitrogen to which it is attached to    form an N-oxide;-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)OR^(7d), (CH₂)_(q)NR^(7a)R^(7a′),    (CH₂)_(r)C(O)R^(7b), (CH₂)_(r)C(O)NR^(7a)R^(7a′),    (CH₂)_(q)NR^(7a)C(O)R^(7a), (CH₂)_(q)NR^(7a)C(O)H,    (CH₂)_(q)S(O)₂NR^(7a)R^(7a′), (CH₂)_(q)NR^(7a)S(O)₂R^(7b),    (CH₂)_(q)NHC(O)NHR^(7a), (CH₂)_(q)NHC(O)OR^(7a),    (CH₂)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(7c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(7c);-   alternatively, R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, ═NR^(8b), or    ═O;-   R⁹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(r)OH, (CH₂)_(r)OR^(9d), (CH₂)_(r)NR^(9a)R^(9a′),    (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a′),    (CH₂)_(r)NR^(9a)C(O)R^(9b), (CH₂)_(r)NR^(9a)C(O)H,    (CH₂)_(r)NR^(9a)C(O)NHR^(9a), (CH₂)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆    haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(9c), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(9c);-   R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl;-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,    (CH₂)_(q)OH, (CH₂)_(q)OR^(11d), (CH₂)_(q)NR^(11a)R^(11a′),    (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a′),    (CH₂)_(q)NR^(11a)C(O)R^(11a), (CH₂)_(q)NR^(11a)C(O)NHR^(11a),    (CH₂)_(q)NHC(O)NHR^(7a), (CH₂)_(q)NHC(O)OR^(7a),    (CH₂)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(11c), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c).

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³,    —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³,    C(═C(CN)₂)NR²R³, and

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁷ is selected from H;-   R¹⁸ is selected from H;-   j is selected from 0, 1, and 2;-   i is selected from 1 and 2;-   s is selected from 0, 1, and 2; and-   g is selected from 0, 1, and 2.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹ is selected from H;-   R² is selected from H; and-   G is selected from —C(O)NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, and    C(═C(CN)₂)NR²R³.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R⁷ is selected from H;-   R⁸ is selected from H; and-   R¹² is selected from H.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r) C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is-   ring D is selected from a C₃₋₆ carbocyclic residue;-   R⁷ is selected from H; and-   R⁸ is selected from H.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, I, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   G is selected from

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹ is selected from H;-   both X¹ and X² cannot be C; and-   Z² is selected from NR^(1′), O, and S.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁷ is selected from H;-   R¹⁸ is selected from H;-   j is selected from 0, 1, and 2;-   i is selected from 1 and 2;-   s is selected from 0, 1, and 2; and-   g is selected from 0, 1, and 2.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R⁷ is selected from H;-   R⁸ is selected from H; and-   R¹² is selected from H.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, I, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In another embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In a further embodimnet, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   E is-   ring D is selected from a C₃₋₆ carbocyclic residue;-   R⁷ is selected from H;-   R⁸ is selected from H.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,    iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    Cl, Br, I, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)C(O)NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b),    (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),    (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and    (CHR′)_(r)phenyl substituted with 0-3 R^(16e);-   R^(16a) and R^(16a′), at each occurrence, are selected from H,    methyl, ethyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted    with 0-2 R^(16e);-   R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F,    Br, I, CN, CF₃, and OCH₃;-   R^(16f), at each occurrence, is selected from H; and-   r is selected from 0, 1, and 2.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein:

-   R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclic residue    substituted with 0-2 R¹⁵;-   R^(3′) and R^(3″), at each occurrence, are selected from H;-   R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆    cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,    (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),    (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b),    (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),    (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);-   R′, at each occurrence, is selected from H, and C₁₋₆ alkyl;-   R^(15a) and R^(15a′), at each occurrence, are selected from H, C₁₋₆    alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5    R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing    1-2 heteroatoms selected from N, O, and S, substituted with 0-2    R^(15e);-   R^(15b), at each occurrence, is selected from C₁₋₆ alkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-2    heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e);    and-   R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br,    I, CN, (CF₂)_(r)CF₃, and OH.

In a further embodiment, the present invention provides a method ofmodulating chemokine receptor by administering a compound of formula(I), wherein the compound is selected from:

-   N-3-[cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   N-3-[trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea;-   (+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea;-   (+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea;-   N-(3-acetylphenyl)-N′-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N′-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(4-fluorophenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea    hydrochloride;-   N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea;-   N-(4-fluorophenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(4-fluorophenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(3-acetylphenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(3-acetylphenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea;-   N-(3-acetylphenyl)-N′-[3-[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]propyl]urea;-   N-(3-acetylphenyl)-N′-[3-[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]propyl]urea;-   N-(3-cyanophenyl)-N′-[3-[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]propyl]urea;    and-   N-(3-cyanophenyl)-N′-[3-[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]propyl]urea.

In another embodiment, E is selected from

In another embodiment, E is selected from

In another embodiment, E is selected from

In another embodiment, E is selected from

In another embodiment, E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹_(R) ¹²).

In another embodiment, E is selected from

In another embodiment, E is selected from

In another embodiment, R⁸, R¹⁰, and R¹² are H.

In another embodiment, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹², are H.

In another embodiment, ring D is selected from a C₃₋₆ carbocyclicresidue.

In another embodiment, ring D is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and phenyl.

In another embodiment, ring D is cyclohexyl.

In another embodiment, G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³,—SO₂NR²R³, —SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, C(═C(CN)₂)NR²R³, and

In another embodiment, G is selected from —C(O)NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³.

In another embodiment, G is selected from —C(O)NR²R³.

In another embodiment, G is selected from

In another embodiment, R¹, R^(1′), and R² are equal to H.

In another embodiment, R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R¹⁵ and a(CR^(3′)CR^(3″))_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, subtituted with 0-3 R¹⁵.

In another embodiment, R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆carbocyclic residue substituted with 0-2 R¹⁵.

In another embodiment, R³ is phenyl substitued with 0-2 R¹⁵.

In another embodiment, R⁴ is absent.

In another embodiment, R¹⁵, at each occurrence, is selected from C₁₋₈alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e).

In another embodiment, the present invention provides a compound offormula (I):A-E-NR¹-G  (I)or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

-   A is selected from-   E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²), and-   ring D is cyclohexyl;-   G is —C(O)NR²R³;-   R¹ ad R² are H;-   R³ is phenyl substituted with 0-3 R¹⁵;-   R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are H;-   R¹⁵ is selected from F and acetyl;-   R¹⁶ is F;-   g is 0;-   s is 1;-   a is 0 or 1;-   b is 1;-   d is 0 or 1;-   c is 0 or 1;-   e is 0; and-   f is 0.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment todescribe additional embodiments of the present invention. Furthermore,any elements of an embodiment are meant to be combined with any and allother elements from any of the embodiments to describe additionalembodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₁₀ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups.“Alkenyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more unsaturated carbon-carbonbonds which may occur in any stable point along the chain, such asethenyl, propenyl, and the like. C₂₋₁₀ alkenyl, is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. C₂₋₁₀ alkynyl, isintended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkynylgroups. “C₃₋₆ cycloalkyl” is intended to include saturated ring groupshaving the specified number of carbon atoms in the ring, includingmono-, bi-, or poly-cyclic ring systems, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C₇cycloalkyl. C₃₋₇ cycloalkyl, is intended to include C₃, C₄, C₅, C₆, andC₇ cycloalkyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

The compounds of Formula I can also be quaternized by standardtechniques such as alkylation of the cyclic amines with an alkyl halideto yield quaternary piperidinium salt products of Formula I. Suchquaternary piperidinium salts would include a counterion. As usedherein, “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 4, 5, 6, or 7-membered monocyclic or bicyclicor 7, 8, 9, or 10-membered bicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated (aromatic), and whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O and S and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom which results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Ifspecifically noted, a nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. As used herein, the term “aromatic heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and 1, 2, 3, or 4 heterotams independentlyselected from the group consisting of N, O and S.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl,piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocyclesinclude, but are not limited to, pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.. . . ) the compounds of the present invention may be delivered inprodrug form. Thus, the present invention is intended to cover prodrugsof the presently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective to modulate chemokine receptoractivity or treat the symptoms of asthma or an allergic disorder in ahost.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are incorporatedin their entirety by reference.

The novel compounds of Formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the edict molecule must becompatible with the reagents and reactions proposed. Not all compoundsof Formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents that are compatible with the reactionconditions will be readily apparent to one skilled in the art andalternate methods must be used. It will also be recognized that anothermajor consideration in the planning of any synthetic route in this fieldis the judicious choice of the protecting group used for the protectionof the reactive funtional groups present in the compounds described inthis invention. An authoritative account describing the manyalternatives to the trained practitioner is Greene and Wuts (ProtectiveGroups in Organic Chemistry, Wiley and Sons, 1991).

Compounds of Formula I, wherein R⁴ is present as defined by the scope,may be prepared by procedures depicted in Scheme 1 from compounds ofFormula I in which R⁴ is absent. It is understood that the chemistry isshown for only one A group of Formula I and that similar transformationsmay be preformed on other A groups. The quaternary salts of Formula Ican be synthesized by alkylation with an alkylhalide such as methyliodide, benzyl bromide, bromoacetate, etc. in a suitable solvent such asTHF, DMF, DMSO, etc. at room temperature to reflux temperature of thesolvent. The N-oxides of Formula I can be made by the general protocolsof Deady, Syn. Comm. 1977, 7, 509 and references therein, with minormodification depending on the substitution of Formula I which should bereadily recognized by one skilled in the art. The N-oxides are createdby oxidation with mCPBA in an inert solvent such as methylene chloride.

The R⁵ shown in the schemes and in Table 1 are representative of thephenyl ring which is a part of ring A in the claims.

Compounds of Formula I may be prepared as shown in Scheme 2. Compoundsin which D is a bond, O or NR¹ may be synthesized by reacting Formula IIwith Formula III, wherein X is a good leaving such as but not limited toCl, Br, or imidazole, in the presence of a base such as, but not limitedto, triethylamine or pyridine. Alternatively, Formula II may be reactedwith an isocyanate of Formula V to provide compounds of Formula I whereG is CONHR³. Alternatively, Formula II may be reacted with Formula IV,wherein X is a good leaving group such as but not limited to Cl, Br, orimidazole, in the presence of a base such as, but not limited to,triethylamine or pyridine to provide compounds of Formula I where G isSO₂R³. Alternatively, Formula II may be reacted with Formulas VI, VII,or VIII wherein X is a good leaving group such as but not limited toethoxide, phenoxide, or methylsulfide to provide compounds of Formula Iaccording to procedures described in Hoffman, et. al. J. Med. Chem.1983, 26, 140 and references therein.

Alternatively, compounds of Formula I can be synthesized by couplingcompounds of Formula II with halogenated heterocycles of Formula IX,where Z¹ and Z² are defined in the scope, as described in Scheme 3. Itis understood that the chemistry is shown for only one A group ofFormula I and heterocycle and that similar transformations may bepreformed on other A groups or halogenated heterocycles. This procedureessentially follows the general procedures of Hong, Y. et. al., Tet.Lett. 1997, 38, 5607 and references therein, with minor modificationdepending on the Formula IX which should be readily recognized by oneskilled in the art. The reaction can be preformed in an inert solventsuch as, but not limited to, toluene at room temperature to the refluxtemperature of the solvent with a Pd-catalyst such as Pd₂(dba)₃ and abase such as sodium t-butoxide. The halogenated heterocycles that arenot commercial available can be synthesized by methods known in the artand are exemplified by, but not limited to, Zou. R., J. Med. Chem. 1997,40, 802.

Preparations of intermediates of Formula II are depicted in Scheme 4.Reductive alkylation of the intermediates of Formula A, whosepreparations are described later if not commercially available, arereacted with compounds of Formula X, whose preparations are describedlater if not commercially available, wherein amine on Formula VII isprotected with protecting group (P) well familiar to those skilled inthe art, and typical examples may be found in Greene, T and Wuts, P. G.M., Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., NewYork, N.Y., 1991 and references therein, is carried out under conditionsknown in the art, for example catalytic hydrogenation with hydrogen inthe presence of palladium or platinum or with reducing agents such assodium triacetoxyborohydride. The protecting group P can be removedusing the appropriate reagents, well familiar to those skilled in theart, and typical examples may be found in Greene, T and Wuts, P. G. M.,which provides the intermediates of Formula II.

Preparations of intermediates of Formula X are described in Scheme 5.Compounds of Formula X can be made from amino alcohols, Formula XI, byprotecting the amine with a suitable protecting (P) under conditionsknown by those skilled in the art. The alcohol can be oxidized to thealdehyde under conditions known in the art; such as but not limited totetrapropylammonium perruthenate and N-methyl morpholine N-oxide inacetonitrile. The amino alcohols that are not commercially available canbe synthesized by methods known in the art and are exemplified by, butnot limited to, Berg et. al., J. Med. Chem. 1998, 41, 1934, Larrow et.al., Chemtracts, 1997, 10, 1058, Palomo et. al., Enantiosel. Synth.B-Amino Acids, 1997, 279, and Yokomatsu et. al., Heterocycles, 1992, 33,1051.

Alternatively, compounds of Formula II can be synthesized by couplingcompounds of Formula A with amino epoxides, Formula XII, as described inScheme 6. It is understood that the chemistry is shown for only one Agroup of Formula I and that similar transformations may be preformed onother A groups. The reaction can be preformed in an inert solvent suchas, but not limited to, DMF, DMSO, or acetonitrile at room temperatureto the reflux temperature of the solvent. The amino protecting group (P)can then be removed under conditions known in the art. The aminoepoxides that are not commercially available can be synthesized bymethods known in the art and are exemplified by, but not limited to,Luly et. al., J. Org. Chem. 1985, 50, 4515.

Alternatively, compounds of Formula II can be synthesized by couplingcompounds of Formula A with intermediates of Formula XIII, see Scheme 7,that have an amine and a leaving group, such as, but not limited to,halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. It isunderstood that the chemistry is shown for only one A group of Formula Iand that similar transformations may be preformed on other A groups. Thereaction can be preformed in an inert solvent such as, but not limitedto, DMF, 2-butanone, or acetonitrile at room temperature to the refluxtemperature of the solvent. The amino protecting group (P) can then beremoved under conditions known in the art. Intermediates of Formula XIIIthat are not commercially available can be synthesized by methods knownin the art.

One embodiment of Formula A, monosubstituted 8-azabicyclo[3.2.1]octanes,2-azabicyclo[2.2.2]octanes, and 7-azabicyclo[2.2.1]heptanes can besynthesized by procedures depicted in Scheme 8. It is understood thatthe chemistry is shown for only one position on2-azabicyclo[2.2.2]octane ring system and that similar transformationsmay be preformed on other ring positions and other azabicycles. FormulaXIV can be treated under Wittig reaction conditions followed byreduction and deprotection to yield compounds of Formula A. Thesesynthetic steps employ reactions well familiar to those skilled in theart and procedures are exemplified in Larock, R. C. ComprehensiveOrganic Transformations, VCH Publishers, New York, 1989 and referencestherein. Compounds of Formula XIV that are not commercially availablecan be synthesized by methods known in the art and are exemplified by,but not limited to, Borne et. al. J. Heterocycl. Chem. 1974, 11, 311 andAggarwal et. al. Tetrahedron, 1999, 55, 293.

Alternatively, monosubstituted 8-azabicyclo[3.2.1]octanes,2-azabicyclo[2.2.2]octanes, and 7-azabicyclo[2.2.1]heptanes can besynthesized by procedures depicted in Scheme 9. It is understood thatthe chemistry is shown for only one position on2-azabicyclo[2.2.2]octane ring system and that similar transformationsmay be preformed on other ring positions and other azabicycles.Compounds of Formula XIV can be treated with a base such as LDA, KHMDS,LHMDS, etc. in THF, ether, dioxane, etc., at −78° C. to room temperatureand an alkylating agent R⁵X where X can be a halide, mesylate, triflate,etc. to yield compounds of Formula XV. The ketone of Formula XV can bereduced to the methylene by methods described by Larock and referencestherein, which are well known to one skilled in the art, to producecompounds of Formula A.

Disubstituted 8-azabicyclo[3.2.1]octanes, 2-azabicyclo[2.2.2]octanes,and 7-azabicyclo[2.2.1]heptanes can be synthesized by proceduresdepicted in Scheme 10 for intermediates of Formula XV. It is understoodthat the chemistry is shown for only one position on the2-azabicyclo[2.2.2]octane ring system and that similar transformationsmay be preformed on other ring positions and other azabicycles.Intermediates of Formula XV can be treated under Wittig reactionconditions followed by reduction and then deprotection of the protectinggroup (P) to produce compounds of Formula A. These synthetic stepsemploy reactions well familiar to those skilled in the art andprocedures are exemplified in Larock, R. C. Comprehensive OrganicTransformations. Alternatively, compounds of Formula XV can be treatedwith a base such as LDA, KHMDS, LHMDS, etc. in THF, ether, dioxane,etc., at −78° C. to room temperature and an alkylating agent R⁶X where Xis a halide, mesylate, triflate, etc. to yield compounds of Formula XVI.The ketone of Formula XVI can be reduced to the methylene by methodsdescribed by Larock and references therein, which are well known to oneskilled in the art, to produce compounds of Formula A.

Another embodiment of Formula A, monosubstituted2-azabicyclo[2.2.2]octanes, and 2-azabicyclo[2.2.1]heptanes can besynthesized by procedures depicted in Scheme 11. It is understood thatthe chemistry is shown for the 2-azabicyclo[2.2.2]octane ring system andthat similar transformations may be preformed to form other azabicycles.Compounds of Formula XVII, which are commercially available, can beprotected on the acid and amino groups under conditions well known toone skilled in the art. Formula XVIII can be treated with a base such asLDA, KHMDS, LHMDS, etc. in THF, ether, dioxane, etc., at −78° C. to roomtemperature and an alkylating agent R⁵X where X is a halide, mesylate,triflate, etc. to yield compounds of Formula XIX. Formula XIX can bedeprotected under conditions well known to one skilled in the art.Cyclization can achieved under dehydrating condition well known in theliterature and exemplified by, but not limited to, Pearlman, W. M. Org.Syn. 1969, 49, 75. The bicycliclactam, Formula XX, can then be reducedto the bicyclicamine of Formula A under conditions well known in the artsuch as, but not limited to, borane in THF at reflux.

Another embodiment of Formula A, the cis- and/ortrans-3a,4,9,9a-tetrahydro-1H-Benz[f]isoindoline and1,2,3,4,4a,5,10,10a-octahydro-Benz[g]isoquinoline ring systems may besynthesized by the intramolecular and intermolecular Diels-Alder routesdepicted in Scheme 12 (see for example, W. Oppolzer et al. Helv. Chim.Acta, 1976, 59, 1186-1202; Neth. Appl. 75 03,392, Sep. 30, 1975 bySandoz, Ltd.). The symbol P can be hydrogen or a protecting group suchas benzyl, trifluoroacetyl, etc., or E or E-Y in precursor or finalform. It to be understood that appropriate functionality may be presentin Formula A, XXI-XXV in precursor or final form and that only theparent unsubstituted molecules are shown in Scheme 12 for sake ofclarity.

Another embodiment of Formula A, the octahydroisoindoles,decahydroisoquinolines and related bicyclic systems, may be synthesizedby an intramolecular Diels-Alder reaction (see for example S. F. Martin,et al., J. Org. Chem. 1983, 48, 5170-5180; Carmosin, et al., U.S. Pat.No. 5,508,424, issued Apr. 16, 1996 to Ortho Pharmaceutical Corp.) asshown in Scheme 13. It to be understood that appropriate functionalitymay be present (such as a substituted or unsubstituted phenyl group, forexample) in Formula A, XXVI-XXX in presursor or final form and that onlythe parent unsubstituted molecules are shown in Scheme 13 for sake ofclarity. The symbol P can be hydrogen or a protecting group such asbenzyl, trifluoroacetyl, etc., or E or E-Y in precursor or final form.

Another embodiment of Formula A, the3a-(phenylmethyl)octahydroisoindoles and other similar bicyclic andtricyclic systems may be synthesized by methods shown in Scheme 14 (seeE. Ciganek, U.S. Pat. No. 5,216,018, issued Jun. 1, 1993 to DuPont MerckPharmaceutical Co.). It is to be understood that appropriatefunctionality may be present in Formula A, XXXI-XXXIII in precursor orfinal form and that only the parent unsubstituted molecules are shown inScheme 14 for sake of clarity. Thus a cyclic anhydride of Formula XXXIwhich is commercially available or can be easily synthesized by methodsfamiliar to one skilled in the art is reacted with benzylamine to yieldimide XXXII. Deprotonation with a strong non-nucleophilic base such asLDA or KHMDS in an inert solvent such as ether or THF followed byquenching with a benzyl bromide, chloride, iodide, tosylate, mesylate,or triflate, yields a benzylated imide which can be reduced to cyclicamine XXXIII. Deprotection yields a cyclic amine of Formula A.

Another embodiment of Formula A, namely compounds containing a fusedcyclobutyl ring can be synthesized as depicted in Scheme 15 (see W.Oppolzer, et ala Helv. Chim. Acta, 1976, 59, 1186-1202; G. Steiner, etal., Heterocycles, 1995, 40, 319-330; Steiner, G. et al., U.S. Pat. No.5,475,105, issued Dec. 12, 1995 to BASF Akt.). It is to be understoodthat appropriate functionality may be present (such as a substituted orunsubstituted phenyl group, for example) in Formula A, XXXIV-XXXVI inprecursor or final form and that only the parent unsubstituted moleculesare shown in Scheme 15 for sake of clarity. The symbol P can be hydrogenor a protecting group such as benzyl, trifluoroacetyl, or E or E-Y inprecursor or final form.

The compounds of this invention and their preparation can be understoodfurther by the following working examples, which do not constitute alimitation of the invention.

EXAMPLES Example 1 Preparation ofN-3-[cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylureaPart A. Preparation ofcis-N-Benzyl-1,2,3,4-tetrahydro-2,3-naphthalenedicarboximide

To a stirred mixture of N-benzylmaleimide (10 g, 53.41 mmol) and zincdust (2 g, 30.59 mmol) in 250 mL DMF was added in a 6 hour period amixture of α,α′-dibromo-o-xylene (23 g, 87.13 mmol) andn-benzylmaleimide (5 g, 26.71 mmol) in 50 mL DMF, as well as sixportions of zinc dust (1 g, 15.30 mmol). The mixture was stirred at roomtemperature for 20 hours, over which time a homogeneous solution wasobserved. The mixture was poured into 1 L water, and 10 mL ofconcentrated hydrochloric acid was added. The solids were removed byfiltration, and the filtrate was extracted with three 500 mL portions ofethyl acetate. The combined extracts were dried over sodium sulfate, andconcentrated to an amber oil which was subjected to flashchromatography, eluting with 50% ethyl acetate/hexanes, followed by 20%methanol/chloroform. The methanol/chloroform fractions were combined andstripped to yield 2.6 g of a yellow oil. This was purified by flashchromatography, eluting with 20% ethyl acetate/toluene to yield 1.0 g ofa white solid as product. Yield=4.2%. NMR (300 MHz, Acetone)δ 7.84-7.79(m, 2H), 7.71-7.66 (m, 2H), 7.14-7.06 (m, 4H), 3.74 (t, 2H, J=7 Hz),2.95-2.90 (m, 2H), 2.74-2.68 (m, 2H), 2.55-2.35 (m, 6H), 1.91-1.80 (m,4H).

Part B. Preparation ofcis-2-benzyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole hydrochloride

A solution of aluminum chloride (0.55 g, 4.2 mmol) in 5 ml of diethylether was added to a 1 M lithium aluminum hydride solution (10 mL, 10mmol) in diethyl ether at 0° C., causing a white solid to precipitate.The mixture was stirred at 0° C. for 20 minutes, thencis-N-benzyl-1,2,3,4-tetrahydro-2,3-naphthalenedicarboximide was addedneat (0.58 g, 2.2 mmol). The mixture was allowed to come to roomtemperature and stirred for 30 minutes, then brought to reflux for 90minutes. The mixture was cooled to 0° C., and the excess aluminumhydrides were destroyed using the Steinhardt procedure (see Fieser andFieser, Reagents for Organic Synthesis; John Wiley & Sons, Inc.: NewYork, N.Y., 1967; p. 584.). The resulting filtrate was diluted with 200mL water, acidified with 1 N hydrochloric acid, and extracted withmethylene chloride. The methylene chloride was stripped, the residue wastaken up in 1 N sodium hydroxide, and the mixture was extracted withchloroform. The combined extracts were dried over sodium sulfate, andstripped to an amber oil. This was diluted with 20 mL of ethyl acetate,and 20 mL of 1 N hydrochloric acid solution in diethyl ether was added.The mixture was extracted with 1 N hydrochloric acid, and the combinedaqueous extracts were washed with a 2:1 mixture of diethyl ether andethyl acetate. The aqueous was then extracted with chloroform, and thecombined extracts were dried over sodium sulfate, and stripped to yield220 mg of a yellow oil as product. Yield=42%. NMR (300 MHz, CDCl₃) δ7.52 (m, 2H), 7.39 (m, 3H), 7.25-7.20 (m, 2H), 7.16-7.12 (m, 2H), 3.92(d, 2H, J=6 Hz), 3.59-3.56 (m, 2H), 3.32 (m, 2H), 2.77 (dd, 2H, J=6 Hz,15 Hz), 2.49 (d, 2H, J=13 Hz), 2.10-2.05 (m, 2H).

Part C. Preparation of cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

To a solution ofcis-2-benzyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole hydrochloride(210 mg, 0.80 mmol) in 10 mL of ethanol was added palladium hydroxide(210 mg, 20 wt % on carbon) and 4 N hydrochloric acid solution indioxane (1 mL, 4 mmol). The mixture was placed on a Parr apparatus, thevessel was pressurized to 50 psi with hydrogen, and the mixture wasshaken for 2 days. TLC of the mixture showed very little reaction, sothe same amounts of palladium hydroxide and hydrochloric acid were addedagain. The vessel was pressurized to 50 psi with hydrogen, and themixture was shaken for an additional 3 days. TLC of the mixture showedthat the reaction was still incomplete, and so the same amounts ofpalladium hydroxide and hydrochloric acid were added, the vessel waspressurized to 50 psi with hydrogen, and the mixture was shaken for anadditional 6 days. The mixture was filtered through celite, and the cakewas rinsed with methanol. The filtrate was stripped, the residue wastaken up in 20 mL of 1 N sodium hydroxide, and the aqueous was extractedwith ethyl acetate. The combined extracts were dried over sodium sulfateand stripped to yield 90 mg of an amber oil, which was purified by flashchromatography, eluting with ethyl acetate followed by 20%methanol/chloroform. Obtained 35 mg of a colorless oil. Yield=25%. NMR(300 MHz, CDCl₃) δ 7.17-7.09 (m, 4H), 3.17-3.16 (m, 2H), 2.79 (bd, 2H,J=9 Hz), 2.58-2.43 (m, 6H), 2.36 (s, 1H).

Part D. Preparation of2-(3-Phthalimido-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

A mixture of cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (32 mg,0.018 mmol), N-(3-bromopropyl)phthalimide (49 mg, 0.18 mmol), potassiumiodide (31 mg, 0.18 mmol), and potassium carbonate (51 mg, 0.37 mmol) in3 mL of methylethyl ketone was heated at reflux for 8 hours. The mixturewas cooled to room temperature, the solids were filtered, and thefiltrate was concentrated in-vacuo. The residue was dry-loaded onto a1×5 cm silica column, and eluted with ethyl acetate followed by 20%methanol/chloroform. Obtained 50 mg of white solids. Yield=78%. NMR (300MHz, CDCl₃) δ 7.84-7.79 (m, 2H), 7.71-7.66 (m, 2H), 7.14-7.06 (m, 4H),3.74 (t, 2H, J=7 Hz), 2.95-2.90 (m, 2H), 2.74-2.68 (m, 2H), 2.55-2.35(m, 6H), 1.91-1.80 (m, 4H).

Part E. Preparation of2-(3-amino-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

Hydrazine (9 mg, 0.28 mmol) was added to a solution of2-(3-Phthalimido-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole(50 mg, 0.14 mmol) in 1 mL of ethanol, and the mixture was refluxed for6 hours. The mixture was cooled to room temperature, and 5 mL of diethylether was added with stirring. After 30 minutes, a white solid hadprecipitated. The solid was collected by filtration, rinsed with diethylether, then stirred in 10 mL of chloroform. The solids were filtered andwashed with chloroform. The filtrate was concentrated to yield 20 mg ofa colorless oil as product. Yield=63%. NMR (300 MHz, CD₃OD) δ 7.09-7.05(m, 4H), 3.03-2.97 (m, 2H), 2.77-2.70 (dd, 2H, J=6 Hz, 14 Hz), 2.68-2.58(m, 4H), 2.50-2.44 (dd, 2H, J=5 Hz, 14 Hz), 2.30 (t, 2H, J=7 Hz), 1.82(t, 2H, J=7 Hz), 1.61 (tt, 2H, J=7 Hz, 8 Hz, 7 Hz).

Part F. Preparation ofN-3-[cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea

To a solution ofN-(3-amino-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole(20 mg, 0.09 mmol) in 1 mL of chloroform was added 3-acetylphenylisocyanate (16 mg, 0.10 mmol). The mixture was stirred overnight, thenapplied directly to a 1×5 cm silica column and eluted with ethyl acetatefollowed by 20% methanol/chloroform. Obtained 27 mg of a yellow, viscousoil as product. Yield=77%. NMR (300 MHz, CD₃OD) δ 7.98 (s, 1H),7.59-7.54 (m, 2H), 7.35 (dd, 1H, J=8 Hz, 8 Hz), 7.12-7.06 (m, 4H), 3.19(t, 2H, J=6 Hz), 3.14 (t, 2H, J=7 Hz, 8 Hz), 2.76 (dd, 2H, J=5 Hz, 15Hz), 2.66 (m, 2H), 2.56 (s, 3H), 2.50 (dd, 2H, J=5, 14), 2.44 (t, 2H,J=8), 1.93 (it, 2H, J=9), 1.75-1.70 (m, 2H).

Example 2 Preparation ofN-3-[trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylureaPart A: Preparation of N-(3-phenylallyl)-allylamine

A solution of cinnamyl bromide (10 g, 50.7 mmol) in 250 mLtetrahydrofuran was added dropwise to a solution of allyl amine (38 ml,507 mmol) in 50 mL tetrahydrofuran at 0° C. the mixture was allowed toslowly come to room temperature then stirred 20 hours. Thetetrahydrofuran was removed in-vacuo, and the residue was partitionedbetween 500 mL of ethyl acetate and 200 ml of water. The layers wereseparated, the organic phase was washed with water followed by brine,then dried over sodium sulfate and concentrated to an amber oil. The oilwas purified by flash chromatography on an 8×15 cm silica column,eluting with 5% methanol/chloroform followed by 10% methanol/chloroform.Obtained 7.2 g of an amber oil as product. Yield=81%. NMR (300 MHz,CDCl₃) δ 7.39-7.20 (m, 5H), 6.54 (d, 1H, J=16 Hz), 6.35-6.26 (m, 1H),6.01-5.87 (m, 1H), 5.24-5.14 (m, 2H), 3.43 (d, 2H, J=7 Hz), 3.31 (d, 2H,J=6 Hz).

Part B. Preparation of N-(3-phenylallyl)-N-allyltrifluoroacetamide

A solution of trifluoroacetic anhydride (1.33 g, 6.35 mmol) in 10 mL ofmethylene chloride was added dropwise to a mixture ofN-(3-phenylallyl)-allylamine (1.0 g, 5.77 mmol) and triethylamine (8.1mL, 57.7 mmol) in 20 ml methylene chloride at 0° C. The mixture wasallowed to come to room temperature and stirred for 16 hours. Themixture was washed with water followed by brine, then dried over sodiumsulfate, and concentrated in-vacuo to an amber oil. The oil was purifiedby flash chromatography, eluting with 10% ethyl acetate/hexanes.Obtained 1.3 g of a colorless oil as product. Yield=84%. NMR (300 MHz,CDCl₃) 6 (7.40-7.24 (m, 5H), 6.53 (d, 1H, J=16 Hz), 6.17-6.03 (m, 1H),5.85-5.72 (m, 1H), 5.34-5.18 (M, 2H), 4.19-4.03 (m, 4H).

Part C. Preparation of cis- andtrans-2-trifluoroacetyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

A solution of N-(3-phenylallyl)-N-allyl-trifluoroacetamide (1.2 g, 4.46mmol) in 13 mL toluene was heated to 235° C. in a sealed tube for 20hours. The mixture was cooled to room temperature and concentrated. Theresidue was purified by flash chromatography on a 3.5×20 cm silicacolumn, eluting with toluene. Obtained 400 mg of white solids whichcontained a 3:2 mixture of trans and cis isomers of the product.Yield=33%. NMR (300 MHz, CDCl₃) δ 7.19-7.12 (m, 4H), 4.15-4.04 (m,1.2H), 3.93-3.84 (m, 0.8H), 3.41-2.92 (m, 4H), 2.77-2.58 (m, 2.7H),2.23-1.99 (m, 1.3H).

Part D. Preparation 2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

To a stirred solution of potassium hydroxide (8.67 g, 154.6 mmol) in 100mL of methanol wastrans-2-trifluoroacetyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole(8.32 g, 30.91 mmol), and the mixture was stirred at room temperaturefor four hours. The mixture was concentrated in-vacuo, and the residuewas partitioned between diethyl ether and water. The layers wereseparated, and the aqueous phase was extracted with three 200 mLportions of diethyl ether. The combined organic phases were dried oversodium sulfate, and concentrated in-vacuo to a yellow oil. The oil waspurified by flash chromatography on an 8×15 cm silica column, elutingwith a 40:10:1 mixture of methylene chloride, methanol, and 25% aqueousammonium hydroxide. Obtained 2.5 g of the trans isomer as a white solid,and 2.0 g of the cis isomer as a pale yellow solid. Yield=46% (trans),37% (cis). NMR (trans) (300 MHz, CDCl₃) δ 7.12 (m, 4H), 3.36-3.31 (m,2H), 3.08-3.03 (m, 2H), 2.71-2.58 (m, 4H), 2.46 (bs, 1H), 1.90 (m, 2H).

Part E. Preparation of2-(3-Phthalimido-n-prop-1-yl)-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

A mixture of trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (200 mg,1.15 mmol), N-(3-bromopropyl)-phthalimide (309 mg, 1.15 mmol), potassiumiodide (192 mg, 1.15 mmol), and potassium carbonate (320 mg, 2.31 mmol)in 10 mL of methylethyl ketone was heated at reflux for 8 hours. Themixture was cooled to room temperature, the solids were filtered, andthe filtrate was concentrated in-vacuo. The residue was dry-loaded ontoa 1×5 cm silica column, and eluted with ethyl acetate followed by 20%methanol/chloroform. Obtained 200 mg of an amber oil. Yield=48%. NMR(300 MHz, CDCl₃) δ 7.87-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.15-7.07 (m,4H), 3.80 (t, 2H, J=7 Hz), 3.22 (m, 2H), 3.01-2.87 (m, 4H), 2.76-2.56(m, 4H), 2.11-1.96 (m, 4H).

Part F. Preparation of2-(3-Amino-n-prop-1-yl)-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole

Hydrazine (42 mg, 1.31 mmol) was added to a solution of2-(3-Phthalimido-n-prop-1-yl)-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole(200 mg, 0.65 mmol) in 5 mL of ethanol, and the mixture was refluxed for20 hours, over which time a white solid had precipitated. The mixturewas cooled to room temperature, the solid was removed by filtration, andthe filtrate was concentrated in-vacuo. The residue was suspended inchloroform, and the solids were removed by filtration. The filtrate wasconcentrated in-vacuo to 90 mg of a yellow oil as product. NMR (300 MHz,CDCl₃) δ 7.16-7.08 (m, 4H), 3.39-3.32 (m, 2H), 3.04-2.98 (m, 6H),2.80-2.61 (m, 4H), 2.08-2.05 (m, 2H), 1.90-1.79 (m, 2H).

Part G. Preparation ofN-3-[trans-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea

To a solution ofN-(3-aminopropyl)-trans-3a,4,9,9a-tetrahydro-benz[f]indoline (90 mg,0.39 mmol) in 2 mL of chloroform was added 3-acetylphenyl isocyanate (70mg, 0.43 mmol), and the mixture was stirred for two days. The crudemixture was purified by flash chromatography on a 1×8 cm silica column,eluting with ethyl acetate followed by 20% methanol/chloroform. Obtained50 mg of white solids as product. NMR (300 MHz, CDCl₃) δ 8.01 (s, 1H),7.65 (d, 1H, J=8 Hz), 7.55 (d, 1H, J=8 Hz), 7.33 (dd, 1H, J=8 Hz, 8 Hz),7.18-7.07 (m, 4H), 3.49-3.41 (m, 2H), 3.34-3.22 (m, 2H), 2.78-2.59 (m,4H), 2.53 (s, 3H), 2.18-1.93 (m, 4H), 1.85-1.79 (m, 2H).

Example 3 Preparation of(+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylureaStep A. Preparation of 3-(4-fluorophenyl)-3-hydroxy-1-propene

A solution of 4-fluorobenzaldehyde (8.5 g, 68.2 mmol, Aldrich) in 50 mLof tetrahydrofuran was added dropwise to a solution of vinylmagnesiumbromide (9.84 g, 75 mmol, Aldrich) in 150 mL of tetrahydrofuran at 0° C.The mixture was stirred for min and then allowed to warm to roomtemperature. The reaction was stirred overnight and quenched by theaddition of water (100 mL). The resulting precipitate was removed byfiltration. The filtrate was concentrated in vacuo and then dissolved in200 mL of ethyl acetate. This solution was washed with water, brine,dried over sodium sulfate, and concentrated in vacuo to 10.3 g of anamber oil as product. NMR (300 MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.04(dd, 2H, J=9 Hz, 9 Hz), 6.08-5.97 (m, 1H), 5.35 (d, 1H, J=17 Hz), 5.21(d, 2H, J=10 Hz), 1.90 (d, 1H, J=4 Hz).

Step B. Preparation of 1-(4-fluorophenyl)-3-chloro-1-propene

A gas dispersion tube was immersed in a solution of3-(4-fluorophenyl)-3-hydroxy-1-propene (1.0 g, 6.57 mmol) in 50 mL oftoluene. Hydrochloric acid gas was bubbled through this solution for 10min, causing a slight exotherm and a brown color. The tube was removedand the solution was diluted with 100 mL of ethyl acetate. This solutionwas washed with water, brine, dried over sodium sulfate and concentratedto 0.9 g of a brown oil as product. NMR (300 MHz, CDCl₃) δ 7.407-7.29(m, 2H), 7.02 (dd, 2H, J=8 Hz, 9 Hz), 6.63 (d, H, J=16 Hz), 6.29-6.19(m, 1H), 4.23 (d, 2H, J=8 Hz).

Part C: Preparation of(+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea

Prepared according to procedures described in Example 2 withmodification at Step A. MS (ESI) 409 (M+H).

Example 4 Preparation of(+/−)-N-3-[trans-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea

Prepared according to procedures described in Example 3 withmodification at last step. MS (ESI) 385 (M+H).

Example 5 Preparation of(+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-3-acetylphenylurea

Prepared according to procedures described in Example 3 withmodification using cis isomer instead of trans. MS (ESI) 409 (M+H).

Example 6 Preparation of(+/−)-N-3-[cis-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindol-2-yl]-n-prop-1-yl-N′-4-fluorophenylurea

Prepared according to procedures described in Example 5 withmodification at last step. MS (ESI) 385 (M+H).

Example 7 Preparation ofN-(3-acetylphenyl)-N′-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride Step A. Preparation of ethyl 4-oxocyclohexanecarboxylate

To a vigorously stirring suspension of ethyl4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol, Aldrich) and activated4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. was sequentially added4-methylmorpholine-N-oxide (2.0 g, 17 mmol) and tetrapropylammoniumperruthenate (410 mg, 1.2 mmol). After stirring the resulting blacksuspension for 30 min, the mixture was concentrated in vacuo, and theresulting residue was filtered through a plug of silica gel (30% ethylacetate in hexanes) to provide ethyl 4-oxocyclohexanecarboxylate as aclear oil (1.93 g, 98%). MS (AP CI) 171 (M+H).

Step B. Preparation of ethyl4-(N,N-di(phenylmethyl)amino)cyclohexanecarboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (1.9 g, 11 mmol) in1,2-dichloroethane (113 mL) at 23° C. was added dibenzylamine (3.4 g,3.3 mL, 17 mmol) in one portion. After 10 min, sodiumtriacetoxyborohydride (4.81 g, 22.7 mmol) was added, and the resultingcloudy suspension was stirred for 48 hrs. The suspension was poured into1N aqueous hydrogen chloride (100 mL), the resulting mixture wasbasified to pH 9.0-10.0 with 12.5 M aqueous sodium hydroxide. The basiclayer was extracted with ethyl acetate (3×50 mL), and the combinedorganic layers were washed with saturated aqueous sodium chloride (70mL), dried over sodium sulfate, and concentrated in vacuo. The resultingresidue was purified by flash chromatography (5-10% ethyl acetate inhexanes) to yield ethyl 4-(N,N-dibenzylamino)cyclohexanecarboxylate (3.4g, 84%) as a clear oil. MS (ESI) 352 (M+H).

Step C. Preparation of ethyl4-(N,N-diphenylmethylamino)-1-(4-(fluorophenyl)methyl)cyclohexane-1-carboxylate

To a stirring solution of diisopropylamine (1.2 g, 1.7 mL, 12 mmol) indry tetrahydrofuran (45 mL) at −78° C. was added 2.5 M n-butyllithium(4.6 mL, 11 mmol) in hexanes. After 3 hr, ethyl4-(N,N-di(phenylmethyl)amino)cyclohexanecarboxylate (3.4 g, 9.5 mmol)was added as a solution in tetrahydrofuran (45 mL) via cannula.

The resulting solution became first pink, then red, and finally orange.After stirring at −78° C. for 3 hr, the reaction was poured intosaturated aqueous sodium chloride (100 mL). The resulting aqueous layerwas extracted with ethyl acetate (3×80 mL), and the combined organiclayers were washed with saturated aqueous sodium chloride (30 mL), driedover sodium sulfate, and concentrated in vacuo. The resulting residuewas purified by flash chromatography to yield exclusively ethyl4-(N,N-di(phenylmethyl)amino)-1-(4-(fluorophenyl)methyl)cyclohexane-1-carboxylate(3.7 g, 85%) with ester and amine functionalities in a cis conformation.The product was a white solid. MS (ESI) 460 (M+H).

Step D. Preparation of ethyl4-amino-1-(4-(fluorophenyl)methyl)cyclohexane-1-carboxylate

To a solution of ethyl4-(N,N-di(phenylmethyl)amino)-1-(4-(fluorophenyl)methyl)cyclohexane-1-carboxylate(1.0 g, 2.2 mmol) in methanol (50 mL) and glacial acetic acid (100 mL)was added 10% palladium on carbon (200 mg, Degussa type) under a streamof nitrogen. The resulting black suspension was shaken vigorously undera hydrogen atmosphere (52 psi) for 48 hrs. The suspension was thenfiltered and the resulting filtrate was concentrated in vacuo. Theresidue was dissolved in a minimal amount of water and poured intosaturated aqueous sodium bicarbonate (30 mL). The resulting aqueouslayer was extracted with ethyl acetate (4×50 mL), and the combinedorganic layers were dried over sodium sulfate and concentrated in vacuoto yield ethyl4-amino-1-(4-(fluorophenyl)methyl)cyclohexane-1-carboxylate as a paleyellow oil. The oil was used directly in step E without furtherpurification. MS (ESI) 280 (M+H).

Step E. Preparation of1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octan-2-one

Neat ethyl 4-amino-1-(4-fluorophenyl)methyl)cyclohexane-1-carboxylatefrom step D in a round bottom flask was heated to 200° C. for 40 minunder an open atmosphere. The resulting brown solid was dissolved in aminimal amount of dichloromethane, and the resulting solution waspurified by flash chromatography (50-100% ethyl acetate in hexanes, then5% methanol in ethyl acetate) to yield ring1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octan-2-one (200 mg, 39%two steps) as a clear oil. MS (ESI) 234 (M+H).

Step F. Preparation ofN-(t-butoxycarbonyl)-1-(4-fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane

To a solution of1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octan-2-one (200 mg, 0.86mmol) in dry tetrahydrofuran (8 mL) at 23° C. was addedborane-tetrahydrofuran (3.4 mL, 3.4 mmol; 1.0 M in tetrahydrofuran).After 10 min, the resulting clear solution was maintained under refluxconditions for 3 hr. The reaction was quenched with 1N aqueous hydrogenchloride (10 mL); this was followed by the addition of a 1-mL portion ofconcentrated hydrogen chloride, and the resulting solution wasmaintained under reflux conditions for 10 min. Upon cooling to 23° C.,the reaction solution was basified to pH 9.0-10.0 with 12.5 M aqueoussodium hydroxide. The aqueous layer was then extracted with ethylacetate (4×60 mL), and the combined organic layers were concentrated invacuo to a colorless oil. The oil was dissolved in tetrahydrofuran (100mL) at 23° C. and to the solution was added di-t-butyl dicarbonate (210mg, 0.94 mmol). After 12 hr, the reaction was concentrated and theresulting residue was purified by flash chromatography (10-20% ethylacetate in hexanes) to yieldN-(t-butoxycarbonyl)-1-(4-fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane(270 mg, 99% two steps). MS (ESI) 320 (M+H).

Step G. Preparation of1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane hydrochloride

To neatN-(t-butoxycarbonyl)-1-(4-fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane(270 mg, 0.85 mmol) was added 4 M hydrogen chloride in dioxane (50 mL).After stirring the resulting pale yellow solution for 30 min, thereaction was concentrated to give1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane hydrochloride (220mg, 100%) as a viscous yellow oil. MS (ESI) 220 (M+H).

Step H. Preparation ofN-3-[N′-(t-butoxycarbonyl)-3-aminopropyl]-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane

To a stirring solution of1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane hydrochloride (220mg, 0.85 mmol) in 1,2-dichloroethane (20 mL) was addedN-(t-butoxycarbonyl)-3-aminopropional (230 mg, 1.3 mmol). After 10 min,sodium triacetoxyborohydride (380 mg, 1.80 mmol) was added in oneportion and the resulting cloudy white mixture was stirred for 72 hr.The reaction was poured into 1N aqueous hydrogen chloride (100 mL), andthe resulting mixture was basified to pH 9.0-10.0 with 12.5 M aqueoussodium hydroxide. The basic layer was extracted with ethyl acetate (3×70mL), and the combined organic layers were washed with saturated aqueoussodium chloride (70 mL), dried over sodium sulfate, and concentrated invacuo. The resulting residue was purified by flash chromatography (100%ethyl acetate—5% methanol, 5% triethylamine in ethyl acetate) to yieldN-3-[N′-(t-butoxycarbonyl)-3-aminopropyl]-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane(320 mg, 100%) as a clear viscous oil. MS (ESI) 377 (M+H).

Step I. Preparation ofN-3-(3-aminopropyl)-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octanedihydrochloride

To neatN-3-[N′-(t-butoxycarbonyl)-3-aminopropyl]-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octane(320 mg, 0.85 mmol) was added 4N hydrogen chloride in dioxane (85 mL).The resulting solution was stirred for 15 min and then concentrated. Theresulting pale yellow oil was redissolved in toluene, and the resultingsolution was again concentrated to giveN-3-(3-aminopropyl)-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octanedihydrochloride (290 mg, 98%) as a white solid. MS (ESI 277 (M+H).

Step J. Preparation ofN-(3-acetylphenyl)-N-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

To a solution ofN-3-(3-aminopropyl)-1-(4-(fluorophenyl)methyl)-3-azabicyclo[2.2.2]octanedihydrochloride (30 mg, 0.086 mmol) in dichloromethane (1 mL) was addedtriethylamine (0.1 mL) and 3-acetylphenylisocyanate (19 mg, 0.12 mmol).After vigorous shaking for 20 s, the yellow solution was concentrated invacuo. The resulting residue was purified by flash chromatography to apale yellow oil. The oil was dissolved in dichloromethane (5 mL) and tothis solution was added 1N hydrogen chloride in diethyl ether (0.14 mL,0.14 mmol). After 5 min, the resulting solution was concentrated invacuo. The resulting residue was redissolved in acetonitrile (1 mL) andwater (7 mL) and lyopholized to giveN′-(3-acetylphenyl)-A-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride (41 mg, 100%) as a white solid. MS (ESI) 438 (M-Cl).

Example 8 Preparation ofN-(4-fluorophenyl)-NA-[3-[1-[(4-fluorophenyl)methyl]-3-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

Prepared according to procedures described in Example 7 withmodification at Step J. MS (ESI) 414 (M-Cl).

Example 9N-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride Step A. Preparation ofN-benzyl-2-azabicyclo[2.2.2]octan-6-one

To a vigorously stirring suspension of(6S)-N-benzyl-2-azabicyclo[2.2.2]octan-6-ol (1.5 g, 6.9 mmol, Maybridge)and activated 4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. wassequentially added 4-methylmorpholine-N-oxide (1.2 g, 10 mmol) andtetrapropylammonium perruthenate (240 mg, 0.69 mmol). After stirring theresulting black suspension for 30 min, the mixture was concentrated invacuo, and the resulting residue was purified by flash chromatography(20-50% ethyl acetate in hexanes) to provideN-benzyl-2-azabicyclo[2.2.2]octan-6-one as an orange oil (1.2 g, 81%).MS (AP CI) 216 (M+H).

Step B. Preparation of6-[4-fluorophenyl)methylene]-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane

To a vigorously stirring suspension ofp-fluorobenzyltriphenylphosphonium chloride (5.7 g, 14 mmol, Aldrich) indry tetrahydrofuran (30 mL) at −78° C. was added 2.5 M n-butyllithium(4.7 mL, 12 mmol) in hexanes via syringe. After 30 min, theorange-yellow mixture was warmed to 0° C., and the suspension becamedeep red. After 5 min, 2-benzyl-2-azabicyclo[2.2.2]octan-6-one (1.2 g,5.6 mmol) was added as a solution in dry tetrahydrofuran (25 mL) viacannula. Upon stirring vigorously for 2.5 hrs, the reaction was pouredinto saturated aqueous sodium chloride (70 mL), and the aqueous layerwas extracted with ethyl acetate (3×70 mL). The combined organic layerswere washed with saturated aqueous sodium chloride (50 mL), dried oversodium sulfate, and concentrated in vacuo. The resulting yellow solidwas purified by flash chromatography (20%-70% ethyl acetate in hexanes)to yield6-[4-fluorophenyl)methylene]-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane(1.7 g, 99%) as a pale yellow oil. MS (ESD 308 (M+H).

Step C. Preparation of6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane acetate

To a solution of6-[4-fluorophenyl)methylene]-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane(800 mg, 2.6 mmol) in methanol (50 mL) and acetic acid (100 mL) wasadded 10% palladium on carbon (160 mg, Degussa type) under a stream ofnitrogen. The resulting black suspension was shaken vigorously for 24hrs before being filtered. The filtrate was concentrated to provide6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane acetate (745 mg,100%) as a pale yellow oil. The oil was used in step D without furtherpurification. MS (ESI) 220 (M+H).

Step D. Preparation of enantiomeric mixture of(1S,4R,6S)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand enantiomeric mixture of(1S,4R,6R)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6S)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane

To a suspension of 6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydroacetate (750 mg, 2.6 mmol) and di-t-butyl dicarbonate (1.3 g, 5.7mmol) in tetrahydrofuran at 23° C. was added saturated aqueous sodiumbicarbonate (30 mL). The resulting cloudy suspension was stirredvigorously for 2 hr and was then poured into saturated aqueous sodiumchloride (100 mL). The aqueous layer was extracted with ethyl acetate(3×70 mL), and the combined organic layers were washed with saturatedaqueous sodium chloride (50 mL), dried over sodium sulfate, andconcentrated in vacuo. The resulting mixture of diasteromeric compoundswere purified and separated by flash chromatography (5-20% ethyl acetatein hexanes) to yield faster-running enantiomeric mixture of(1S,4R,6S)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane(180 mg, 24%) and slower-enantiomeric mixture of(1S,4R,6R)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6S)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane(300 mg, 40%) as clear oils. MS (ESI) 320 (6S, M+H), 320 (6R, M+H).

Step E. Preparation of(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride and(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride

To neat(1S,4R,6S)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-N-(t-butoxycarbonyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octane(180 mg, 0.57 mmol) was added 4N hydrogen chloride in dioxane (40 mL).The resulting yellow solution was stirred for min and was thenconcentrated. The residue was further concentrated under high-vacuum for20 min to yield(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride and(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride (150 mg, 100%) as a highly viscous yellow oil that wasused in step F without further purification. MS (ESI) 220 (M+H).

Step F. Preparation of(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octane.

To a stirring solution of(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride and(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanehydrochloride (150 mg, 0.57 mmol) in 1,2-dichloroethane (8 mL) at 23° C.was added N-(t-butoxycarbonyl)-3-aminopropional (220 mg, 1.3 mmol).After 10 min, sodium triacetoxyborohydride (350 mg, 1.7 mmol) was addedin one portion, and the resulting suspension was stirred for 6 hr. Thereaction was then poured into 1N aqueous hydrogen chloride (50 mL), andthe resulting mixture was basified to pH 9.0-10.0 with 12.5 M aqueoussodium hydroxide. The basic layer was extracted with ethyl acetate (3×50mL), and the combined organic layers were washed with saturated aqueoussodium chloride (70 mL), dried over sodium sulfate, and concentrated invacuo. The resulting residue was purified by flash chromatography (10%methanol in dichloromethane then 5% triethylamine, 10% methanol indichloromethane) to yield(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octane(68 mg, 0.18 mmol) as a pale yellow oil. MS (ESI) 377 (M+H).

Step G. Preparation of(1S,4R,6S)-2-(3-aminopropyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanedihydrochloride and(1R,4S,6R)-2-(3-aminopropyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanedihydrochloride

To neat(1S,4R,6S)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octaneand(1R,4S,6R)-6-(4-(fluorophenyl)methyl)-2-(N-(t-butoxycarbonyl)-3-aminopropyl)-2-azabicyclo[2.2.2]octane(68 mg, 0.18 mmol) was added 4N hydrogen chloride (20 mL). The yellowsolution was stirred for 1 hr and was then concentrated. The resultingresidue (63 mg, 100%) was used directly in the next step without furtherpurification. MS (ESI) 277 (M+H).

Step H. Preparation ofN-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureaandN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea

To a solution of(1S,4R,6S)-2-(3-aminopropyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanedihydrochloride and(1R,4S,6R)-2-(3-aminopropyl)-6-(4-(fluorophenyl)methyl)-2-azabicyclo[2.2.2]octanedihydrochloride (63 mg, 0.09 mmol) and triethylamine (100 μL) indichloromethane (1 mL) was added 3-acetylphenylisocyanate (16 mg, 0.10mmol). The yellow solution was shaken vigorously for 20 s and was thenconcentrated in vacuo. The resulting residue was purified by flashchromatography (100% ethyl acetate then 5% methanol, 10% triethylaminein ethyl acetate) to yieldN-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureaandN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea(8.5 mg, 23%) as a pale yellow oil. MS (ESI) 438 (M+H).

Step I. Preparation ofN-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

To a solution ofN-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureaandN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]urea(8.5 mg, 0.019 mmol) in dichloromethane (10 mL) was added 1N hydrogenchloride in diethyl ether (21 μL, 0.021 mmol). The resulting suspensionwas stirred for 10 min and was then concentrated. The residue wasdissolved in acetonitrile (1 mL) and water (7 mL) and lyopholized toaffordN-(3-acetylphenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(3-acetylphenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride (9.0 mg, 100%) as an amorphous solid. MS (ESI) 438 (M-Cl).

Example 10N-(4-fluorophenyl)-N′-[3-[(1S,4R,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(4-fluorophenyl)-N′-[3-[(1R,4S,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

Prepared according to procedures described in Example 9 withmodification at Step H. MS (ESI) 414 (M-Cl).

Example 11N-(3-acetylphenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(3-acetylphenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

Prepared according to procedures described in Example 9 withmodification at Step D. MS (ESI) 438 (M-Cl).

Example 12N-(4-fluorophenyl)-N′-[3-[(1S,4R,6R)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride andN-(4-fluorophenyl)-N′-[3-[(1R,4S,6S)-6-[(4-fluorophenyl)methyl]-2-azabicyclo[2.2.2]oct-2-yl]propyl]ureahydrochloride

Prepared according to procedures described in Example 9 withmodification at Step D. MS (ESI) 414 (M-Cl).

Example 13N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea.Step A. Preparation ofN-(t-butoxycarbonyl)-3-[(4-fluorophenyl)methylene]-8-azabicyclo[3.2.1]octane

To a vigorously stirring suspension of4-fluorobenzyltriphenylphosphonium chloride (4.96 g, 12.2 mmol) intetrahydrofuran 25 mL) at −78° C. was added 2.5 M n-butyllithium (4.12mL, 10.3 mmol) in hexanes. The resulting yellow suspension wasmaintained at −78° C. for 25 min and was then warmed to 0° C. After 30min, N-(t-butoxycarbonyl)-nortropinone (1.1 g, 4.9 mmol) was added tothe now red suspension as a solution in tetrahydrofuran (25 mL). Thesuspension changed color from red to orange, and the reaction was heatedto 80° C. The reaction was maintained at reflux conditions for 60 hrsprior to being quenched with saturated aqueous ammonium chloride (30mL). The layers were separated, and the aqueous layer was washed withethyl acetate (3×30 mL). The combined organic layers were dried oversodium sulfate, concentrated in vacuo, and the resulting residue waspurified by flash column chromatography (10-30% ethyl acetate inhexanes) toN-(t-butoxycarbonyl)-3-[(4-fluorophenyl)methylene]-8-azabicyclo[3.2.1]octane(1.37 g, 88%) as a white solid. MS (ESI) 218 (M+H).

Step B. Preparation ofN-(t-butoxycarbonyl)-(3-exo)-3-[(4-fluorophenylmethyl]-8-azabicyclo[3.2.1]octaneandN-(t-butoxycarbonyl)-(3-endo)-3-[(4-fluorophenylmethyl]-8-azabicyclo[3.2.1]octane.

To a solution ofN-(t-butoxycarbonyl)-3-[(4-fluorophenyl)methylene]-8-azabicyclo[3.2.1]octane(300 mg, 0.95 mmol) in methanol was added 10% palladium on carbon (60mg, Degussa type) under a nitrogen atmosphere. The resulting blacksuspension was subjected to a hydrogen atmosphere (51 psi) for 14 hrs,and the reaction was then filtered, and the filtrate was concentrated invacuo to yield a 2.6:1.0 mixture of endo:exo isomers as determined by¹H-NMR. Separation of exo and endo isomers by high-performance liquidchromatography using a Chiralpak AD column (10% acetonitrile and 90%CO₂) yieldingN-(t-butoxycarbonyl)-(3-exo)-3-[(4-fluorophenylmethyl]-8-azabicyclo[3.2.1]octane(84 mg) as a colorless oil andN-(t-butoxycarbonyl)-(3-exo)-3-[(4-fluorophenylmethyl]-8-azabicyclo[3.2.1]octane(166 mg) as a colorless oil. MS (AP CI) 320 (M+H).

Step C. Preparation of(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]octanehydrochloride

To neatN-(t-butoxycarbonyl)-(3-exo)-3-[(4-fluorophenylmethyl]-8-azabicyclo[3.2.1]octane(120 mg, 0.38 mmol) was added 4 M hydrogen chloride in dioxane (30 mL,120 mmol). After stirring for 30 min, the resulting pale yellow solutionwas concentrated in vacuo to provide(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]octanehydrochloride (96 mg, 100%) as a pale yellow oil. MS (AP CI) 220 (M+H).

Step D. Preparation ofN-(benzyloxycarbonyl)-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-amino-cyclohexane

Dichloroethane (4 mL) was added to(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]octanehydrochloride (96 mg, 0.38 mmol) followed by the sequential addition of(1R,2R)-N-(benzyloxycarbonyl)-2-formylcyclohexylamine (128 mg, 0.49mmol). The resulting solution was maintained at 23° C. for 5 min.Following the addition of sodium triacetoxyborohydride (159 mg, 0.75mmol) in one portion, the resulting white suspension was stirred for 12hr and then added to aqueous 1N hydrogen chloride (30 mL). The aqueouslayer was basified with aqueous 12.5N sodium hydroxide (3 mL), and thelayers were separated. The aqueous layer was extracted with ethylacetate (3×40 mL), and the combined organic layers were washed withsaturated aqueous sodium chloride (10 mL) and dried over sodium sulfate.Upon concentration in vacuo, the resulting residue was purified by flashcolumn chromatography (10% methanol in dichloromethane) to giveN-(benzyloxycarbonyl)-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-amino-cyclohexane.(145 mg, 83%) as a pale yellow oil. MS (ESI) 465 (M+H).

Step E. Preparation of(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-amino-cyclohexanediacetate

ToN-(benzyloxycarbonyl)-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-amino-cyclohexanewas added methanol (100 mL) and glacial acetic acid (10 mL) prior to theaddition of 10% palladium on carbon (50 mg, Degussa type) under anitrogen atmosphere. The resulting black suspension was subjected to ahydrogen atmosphere (50 psi) with vigorous shaking for 4 hrs. Thesuspension was then filtered, and the filtrate was concentrated in vacuoto provide(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-amino-cyclohexanediacetate as a pale brown oil (140 mg, 100%). MS (ESI) 331 (M+H).

Step F. Preparation ofN-(3-acetylphenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea

To a solution of(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(1R)-1-cyclohexyl]aminediacetate (30 mg, 0.091 mmol) and triethylamine (100 μL, 0.72 mmol) indichloromethane (2 mL) was added 3-acetylphenylisocyanate (16 mg, 0.10mmol). The resulting pale yellow solution was shaken for 20 s and thenconcentrated. The resulting residue was purified by flash columnchromatography (0 to 5% triethylamine in ethyl acetate) to giveN-(3-acetylphenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]ureaas a pale yellow oil (18 mg, 40%). MS (ESI) 492 (M-Cl).

Example 14N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-exo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea

Prepared according to procedures described in Example 13 withmodification at Step F. MS (ESI) 468 (M-Cl).

Example 15N-(3-acetylphenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea

Prepared according to procedures described in Example 13 using endoinstead of exo isomer. MS (ESI) 492 (M-Cl).

Example 16N-(4-fluorophenyl)-N′-[(2S)-2-[[(3-endo)-3-[(4-fluorophenyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl]methyl]-(2R)-1-cyclohexyl]urea

Prepared according to procedures described in Example 15 withmodification at Step F. MS (ESI) 468 (M-Cl).

Example 17N-(3-acetylphenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}ureaandN-(3-acetylphenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea

A racemic mixture of(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane and(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane (Steiner, G.,Nunschauer, R., Klebe, G., Siggel, L. Heterocycles, 1995, 40,319-330)was converted to the titled compounds using the proceduresdescribed in Example 1, parts D, E, and F. MS (ESI) 410 (M+H).

Example 18N-(4-fluorophenyl)-N′-{3-[(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}ureaandN-(4-fluorophenyl)-N′-{3-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]propyl}urea

A racemic mixture of(1S,5R,6R)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane and(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.2.0]heptane (Steiner, G.,Nunschauer, R., Klebe, G., Siggel, L. Heterocycles, 1995, 40,319-330)was converted to the titled compounds using the proceduresdescribed in Example 1, parts D, E, and F, where instead of3-acetylisocyanate in part F, 4-fluorophenylisocyanate was used instead.MS (ESI) 386 (M+H).

The following table contains representative examples of the presentinvention. Each entry in the table is intended to be paired with eachformulae at the start of the table. For example, entry 1 in Table 1 isintended to be paired with a-h. TABLE 1 a

b

c

d

e

f

g

h

ENTRY R5 R3 1 4-F-Ph Ph 2 4-F-Ph 3-CN-Ph 3 4-F-Ph 3-COCH3-Ph 4 4-F-Ph3-CO2Me-Ph 5 4-F-Ph 3-CO2Et-Ph 6 4-F-Ph 3-CO2H-Ph 7 4-F-Ph 3-CONH2-Ph 84-F-Ph 3-CONHMe-Ph 9 4-F-Ph 3-F-Ph 10 4-F-Ph 3-Cl-Ph 11 4-F-Ph 3-Br-Ph12 4-F-Ph 3-NO2-Ph 13 4-F-Ph 3-NH2-Ph 14 4-F-Ph 3-NHMe-Ph 15 4-F-Ph3-NMe2 -Ph 16 4-F-Ph 3-NHCOCH3-Ph 17 4-F-Ph 3-SO2NH2-Ph 18 4-F-Ph3-SO2NHMe-Ph 19 4-F-Ph 3-CF3-Ph 20 4-F-Ph 3-OCH3-Ph 21 4-F-Ph 3-OPh-Ph22 4-F-Ph 3-OCF3-Ph 23 4-F-Ph 3-SCH3-Ph 24 4-F-Ph 3-SOCH3-Ph 25 4-F-Ph3-SO2CH3-Ph 26 4-F-Ph 3-OH-Ph 27 4-F-Ph 3-CH2OH-Ph 28 4-F-Ph3-CHOHCH3-Ph 29 4-F-Ph 3-COH(CH3)2-Ph 30 4-F-Ph 3-CHOHPh-Ph 31 4-F-Ph3-CH3-Ph 32 4-F-Ph 3-C2H5-Ph 33 4-F-Ph 3-iPr-Ph 34 4-F-Ph 3-tBu-Ph 354-F-Ph 3-Ph-Ph 36 4-F-Ph 3-CH2Ph-Ph 37 4-F-Ph 3-CH2CO2Me-Ph 38 4-F-Ph3-(1-piperidinyl)-Ph 39 4-F-Ph 3-(1-pyrrolidinyl)-Ph 40 4-F-Ph3-(2-imidazolyl)-Ph 41 4-F-Ph 3-(1-imidazolyl)-Ph 42 4-F-Ph3-(2-thiazolyl)-Ph 43 4-F-Ph 3-(3-pyrazolyl)-Ph 44 4-F-Ph3-(1-pyrazolyl)-Ph 45 4-F-Ph 3-(1-tetrazolyl)-Ph 46 4-F-Ph3-(5-tetrazolyl)-Ph 47 4-F-Ph 3-(2-pyridyl)-Ph 48 4-F-Ph3-(2-thienyl)-Ph 49 4-F-Ph 3-(2-furanyl)-Ph 50 4-F-Ph 4-CN-Ph 51 4-F-Ph4-COCH3-Ph 52 4-F-Ph 4-CO2Me-Ph 53 4-F-Ph 4-CO2Et-Ph 54 4-F-Ph 4-CO2H-Ph55 4-F-Ph 4-CONH2-Ph 56 4-F-Ph 4-CONHMe-Ph 57 4-F-Ph 4-CONHPh-Ph 584-F-Ph 4-NHCONH2-Ph 59 4-F-Ph 4-F-Ph 60 4-F-Ph 4-Cl-Ph 61 4-F-Ph 4-Br-Ph62 4-F-Ph 4-NO2-Ph 63 4-F-Ph 4-NH2-Ph 64 4-F-Ph 4-NHMe-Ph 65 4-F-Ph4-NMe2-Ph 66 4-F-Ph 4-NHCOCH3-Ph 67 4-F-Ph 4-SO2NH2-Ph 68 4-F-Ph4-SO2NHMe-Ph 69 4-F-Ph 4-CF3-Ph 70 4-F-Ph 4-OCH3-Ph 71 4-F-Ph 4-OPh-Ph72 4-F-Ph 4-OCF3-Ph 73 4-F-Ph 4-SCH3-Ph 74 4-F-Ph 4-SOCH3-Ph 75 4-F-Ph4-SO2CH3-Ph 76 4-F-Ph 4-OH-Ph 77 4-F-Ph 4-CH2OH-Ph 78 4-F-Ph4-CHOHCH3-Ph 79 4-F-Ph 4-COH(CH3)2-Ph 80 4-F-Ph 4-CH3-Ph 81 4-F-Ph4-C2H5-Ph 82 4-F-Ph 4-iPr-Ph 83 4-F-Ph 4-tBu-Ph 84 4-F-Ph 4-Ph-Ph 854-F-Ph 4-CH2Ph-Ph 86 4-F-Ph 4-CH2CO2Me-Ph 87 4-F-Ph 4-(1-piperidinyl)-Ph88 4-F-Ph 4-(1-pyrrolidinyl)-Ph 89 4-F-Ph 4-(2-imidazolyl)-Ph 90 4-F-Ph4-(1-imidazolyl)-Ph 91 4-F-Ph 4-(2-thiazolyl)-Ph 92 4-F-Ph4-(3-pyrazolyl)-Ph 93 4-F-Ph 4-(1-pyrazolyl)-Ph 94 4-F-Ph4-(1-tetrazolyl)-Ph 95 4-F-Ph 4-(5-tetrazolyl)-Ph 96 4-F-Ph4-(2-pyridyl)-Ph 97 4-F-Ph 4-(2-thienyl)-Ph 98 4-F-Ph 4-(2-furanyl)-Ph99 4-F-Ph 2-CN-Ph 100 4-F-Ph 2-COCH3-Ph 101 4-F-Ph 2-CO2Me-Ph 102 4-F-Ph2-CO2Et-Ph 103 4-F-Ph 2-CO2H-Ph 104 4-F-Ph 2-CONH2-Ph 105 4-F-Ph2-CONHMe-Ph 106 4-F-Ph 2-F-Ph 107 4-F-Ph 2-Cl-Ph 108 4-F-Ph 2-Br-Ph 1094-F-Ph 2-NO2-Ph 110 4-F-Ph 2-NH2-Ph 111 4-F-Ph 2-NHMe-Ph 112 4-F-Ph2-NMe2-Ph 113 4-F-Ph 2-NHCOCH3-Ph 114 4-F-Ph 2-SO2NH2-Ph 115 4-F-Ph2-SO2NHMe-Ph 116 4-F-Ph 2-CF3-Ph 117 4-F-Ph 2-OCH3-Ph 118 4-F-Ph2-OPh-Ph 119 4-F-Ph 2-OCF3-Ph 120 4-F-Ph 2-SCH3-Ph 121 4-F-Ph 2-SOCH3-Ph122 4-F-Ph 2-SO2CH3-Ph 123 4-F-Ph 2-OH-Ph 124 4-F-Ph 2-CH2OH-Ph 1254-F-Ph 2-CHOHCH3-Ph 126 4-F-Ph 2-COH(CH3)2-Ph 127 4-F-Ph 2-CHOHPh-Ph 1284-F-Ph 2-CH3-Ph 129 4-F-Ph 2-C2H5-Ph 130 4-F-Ph 2-iPr-Ph 131 4-F-Ph2-tBu-Ph 132 4-F-Ph 2-Ph-Ph 133 4-F-Ph 2-CH2Ph-Ph 134 4-F-Ph2-CH2CO2Me-Ph 135 4-F-Ph 2-(1-piperidinyl)-Ph 136 4-F-Ph2-(1-pyrrolidinyl)-Ph 137 4-F-Ph 2-(2-imidazolyl)-Ph 138 4-F-Ph2-(1-imidazolyl)-Ph 139 4-F-Ph 2-(2-thiazolyl)-Ph 140 4-F-Ph2-(3-pyrazolyl)-Ph 141 4-F-Ph 2-(1-pyrazolyl)-Ph 142 4-F-Ph2-(1-tetrazolyl)-Ph 143 4-F-Ph 2-(5-tetrazolyl)-Ph 144 4-F-Ph2-(2-pyridyl)-Ph 145 4-F-Ph 2-(2-thienyl)-Ph 146 4-F-Ph 2-(2-furanyl)-Ph147 4-F-Ph 2,4-diF-Ph 148 4-F-Ph 2,5-diF-Ph 149 4-F-Ph 2,6-diF-Ph 1504-F-Ph 3,4-diF-Ph 151 4-F-Ph 3,5-diF-Ph 152 4-F-Ph 2,4-diCl-Ph 1534-F-Ph 2,5-diCi-Ph 154 4-F-Ph 2,6-diCi-Ph 155 4-F-Ph 3,4-diCl-Ph 1564-F-Ph 3,5-diCl-Ph 157 4-F-Ph 3,4-diCF3-Ph 158 4-F-Ph 3,5-diCF3-Ph 1594-F-Ph 5-Cl-2-MeO-Ph 160 4-F-Ph 5-C1-2-Me-Ph 161 4-F-Ph 2-F-5-Me-Ph 1624-F-Ph 2-F-5-NO2-Ph 163 4-F-Ph 3,4-OCH2O-Ph 164 4-F-Ph 3,4-OCH2CH2O-Ph165 4-F-Ph 2-MeO-4-Me-Ph 166 4-F-Ph 2-MeO-5-Me-Ph 167 4-F-Ph 1-naphthyl168 4-F-Ph 2-naphthyl 169 4-F-Ph 2-thienyl 170 4-F-Ph 3-thienyl 1714-F-Ph 2-furanyl 172 4-F-Ph 3-furanyl 173 4-F-Ph 2-pyridyl 174 4-F-Ph3-pyridyl 175 4-F-Ph 4-pyridyl 176 4-F-Ph 2-indolyl 177 4-F-Ph 3-indolyl178 4-F-Ph 5-indolyl 179 4-F-Ph 6-mdolyl 180 4-F-Ph 3-indazolyl 1814-F-Ph 5-indazolyl 182 4-F-Ph 6-indazolyl 183 4-F-Ph 2-imidazolyl 1844-F-Ph 3-pyrazolyl 185 4-F-Ph 2-thiazolyl 186 4-F-Ph 5-tetrazolyl 1874-F-Ph 2-benzimidazolyl 188 4-F-Ph 5-benzimidazolyl 189 4-F-Ph2-benzothiazolyl 190 4-F-Ph 5-benzothiazolyl 191 4-F-Ph 2-benzoxazolyl192 4-F-Ph 5-benzoxazolyl 193 2-F-Ph 3-CN-Ph 194 2-F-Ph 3-COCH3-Ph 1952-F-Ph 3-CO2Me-Ph 196 2-F-Ph 3-CO2Et-Ph 197 2-F-Ph 3-CO2H-Ph 198 2-F-Ph3-CONH2-Ph 199 2-F-Ph 3-F-Ph 200 2-F-Ph 3-Cl-Ph 201 2-F-Ph 3-NH2-Ph 2022-F-Ph 3-SO2NH2-Ph 203 2-F-Ph 3-CF3-Ph 204 2-F-Ph 3-OCH3-Ph 205 2-F-Ph3-OEt-Ph 206 2-F-Ph 3-OCF3-Ph 207 2-F-Ph 3-SO2CH3-Ph 208 2-F-Ph 3-OH-Ph209 2-F-Ph 3-CH3-Ph 210 2-F-Ph 3-C2H5-Ph 211 2-F-Ph 4-CN-Ph 212 2-F-Ph4-COCH3-Ph 213 2-F-Ph 4-CO2Me-Ph 214 2-F-Ph 4-CO2Et-Ph 215 2-F-Ph4-CO2H-Ph 216 2-F-Ph 4-CONH2-Ph 217 2-F-Ph 4-F-Ph 218 2-F-Ph 4-Cl-Ph 2192-F-Ph 4-NH2-Ph 220 2-F-Ph 4-SO2NH2-Ph 221 2-F-Ph 4-CF3-Ph 222 2-F-Ph4-OCH3-Ph 223 2-F-Ph 4-OEt-Ph 224 2-F-Ph 4-OCF3-Ph 225 2-F-Ph4-SO2CH3-Ph 226 2-F-Ph 4-OH-Ph 227 2-F-Ph 4-CH3-Ph 228 2-F-Ph 4-C2H5-Ph229 2-F-Ph 2,4-diF-Ph 230 2-F-Ph 2,5-diF-Ph 231 2-F-Ph 3,4-diF-Ph 2322-F-Ph 3,5-diF-Ph 233 2-F-Ph 2,4-diCl-Ph 234 2-F-Ph 2,5-diCl-Ph 2352-F-Ph 3,4-diCl-Ph 236 2-F-Ph 3,5-diCl-Ph 237 2-F-Ph 3,4-OCH2O-Ph 2382-F-Ph 3,4-OCH2CH2O-Ph 239 2-F-Ph 2-thienyl 240 2-F-Ph 2-furanyl 2412-F-Ph 2-pyridyl 242 2-F-Ph 4-pyridyl 243 2-F-Ph 2-imidazolyl 244 2-F-Ph3-pyrazolyl 245 2-F-Ph 2-thiazolyl 246 2-F-Ph 5-tetrazolyl 247 2-F-Ph1-adamantyl 248 2,4-diF-Ph 3-CN-Ph 249 2,4-diF-Ph 3-COCH3-Ph 2502,4-diF-Ph 3-CO2Me-Ph 251 2,4-diF-Ph 3-CO2Et-Ph 252 2,4-diF-Ph 3-CO2H-Ph253 2,4-diF-Ph 3-CONH2-Ph 254 2,4-diF-Ph 3-F-Ph 255 2,4-diF-Ph 3-Cl-Ph256 2,4-diF-Ph 3-NH2-Ph 257 2,4-diF-Ph 3-SO2NH2-Ph 258 2,4-diF-Ph3-CF3-Ph 259 2,4-diF-Ph 3-OCH3-Ph 260 2,4-diF-Ph 3-OEt-Ph 261 2,4-diF-Ph3-OCF3-Ph 262 2,4-diF-Ph 3-SO2CH3-Ph 263 2,4-diF-Pli 3-OH-Ph 2642,4-diF-Ph 3-CH3-Ph 265 2,4-diF-Ph 3-C2H5-Ph 266 2,4-diF-Ph 4-CN-Ph 2672,4-diF-Ph 4-COCH3-Ph 268 2,4-diF-Ph 4-CO2Me-Ph 269 2,4-diF-Ph4-CO2Et-Ph 270 2,4-diF-Ph 4-CO2H-Ph 271 2,4-diF-Ph 4-CONH2-Ph 2722,4-diF-Ph 4-F-Ph 273 2,4-diF-Ph 4-Cl-Ph 274 2,4-diF-Ph 4-NH2-Ph 2752,4-diF-Ph 4-SO2NH2-Ph 276 2,4-diF-Ph 4-CF3-Ph 277 2,4-diF-Ph 4-OCH3-Ph278 2,4-diF-Ph 4-OEt-Ph 279 2,4-diF-Ph 4-OCF3-Ph 280 2,4-diF-Ph4-SO2CH3-Ph 281 2,4-diF-Ph 4-OH-Ph 282 2,4-diF-Ph 4-CH3-Ph 2832,4-diF-Ph 4-C2H5-Ph 284 2,4-diF-Ph 2,4-diF-Ph 285 2,4-diF-Ph 2,5-diF-Ph286 2,4-diF-Ph 3,4-diF-Ph 287 2,4-diF-Ph 3,5-diF-Ph 288 2,4-diF-Ph2,4-diCl-Ph 289 2,4-diF-Ph 2,5-diCl-Ph 290 2,4-diF-Ph 3,4-diCl-Ph 2912,4-diF-Ph 3,5-diCl-Ph 292 2,4-diF-Ph 3,4-OCH2O-Ph 293 2,4-diF-Ph3,4-OCH2CH2O-Ph 294 2,4-diF-Ph 2-thienyl 295 2,4-diP-Ph 2-furanyl 2962,4-diP-Ph 2-pyridyl 297 2,4-diF-Ph 4-pyridyl 298 2,4-diF-Ph2-imidazolyl 299 2,4-diF-Ph 3-pyrazolyl 300 2,4-diF-Ph 2-thiazolyl 3012,4-diF-Ph 5-tetrazolyl 302 4-Cl-Ph Ph 303 4-Cl-Ph 3-CN-Ph 304 4-Cl-Ph3-COCH3-Ph 305 4-Cl-Ph 3-CO2Me-Ph 306 4-Cl-Ph 3-CO2Et-Ph 307 4-Cl-Ph3-CO2H-Ph 308 4-Cl-Ph 3-CONH2-Ph 309 4-Cl-Ph 3-CONHMe-Ph 310 4-Cl-Ph3-F-Ph 311 4-Cl-Ph 3-Cl-Ph 312 4-Cl-Ph 3-Br-Ph 313 4-Cl-Ph 3-NO2-Ph 3144-Cl-Ph 3-NH2-Ph 315 4-Cl-Ph 3-NHMe-Ph 316 4-Cl-Ph 3-NMe2-Ph 317 4-Cl-Ph3-NHCOCH3-Ph 318 4-Cl-Ph 3-SO2NH2-Ph 319 4-Cl-Ph 3-SO2NHMe-Ph 3204-Cl-Ph 3-CF3-Ph 321 4-Cl-Ph 3-OCH3-Ph 322 4-Cl-Ph 3-OPh-Ph 323 4-Cl-Ph3-OCF3-Ph 324 4-Cl-Ph 3-SCH3-Ph 325 4-Cl-Ph 3-SOCH3-Ph 326 4-Cl-Ph3-SO2CH3-Ph 327 4-Cl-Ph 3-OH-Ph 328 4-Cl-Ph 3-CH2OH-Ph 329 4-Cl-Ph3-CHOHCH3-Ph 330 4-Cl-Ph 3-COH(CH3)2-Ph 331 4-Cl-Ph 3-CHOHPh-Ph 3324-Cl-Ph 3-CH3-Ph 333 4-Cl-Ph 3-C2H5-Ph 334 4-Cl-Ph 3-iPr-Ph 335 4-Cl-Ph3-tBu-Ph 336 4-Cl-Ph 3-Ph-Ph 337 4-Cl-Ph 3-CH2Ph-Ph 338 4-Cl-Ph3-CH2CO2Me-Ph 339 4-Cl-Ph 3-(1-piperidinyl)-Ph 340 4-Cl-Ph3-(1-pyrrolidinyl)-Ph 341 4-Cl-Ph 3-(2-imidazolyl)-Ph 342 4-Cl-Ph3-(1-imidazolyl)-Ph 343 4-Cl-Ph 3-(2-thiazolyl)-Ph 344 4-Cl-Ph3-(3-pyrazolyl)-Ph 345 4-Cl-Ph 3-(1-pyrazolyl)-Ph 346 4-Cl-Ph3-(1-tetrazolyl)-Ph 347 4-Cl-Ph 3-(5-tetrazolyl)-Ph 348 4-Cl-Ph3-(2-pyridyl)-Ph 349 4-Cl-Ph 3-(2-thienyl)-Ph 350 4-Cl-Ph3-(2-furanyl)-Ph 351 4-Cl-Ph 4-CN-Ph 352 4-Cl-Ph 4-COCH3-Ph 353 4-Cl-Ph4-CO2Me-Ph 354 4-Cl-Ph 4-CO2Et-Ph 355 4-Cl-Ph 4-CO2H-Ph 356 4-Cl-Ph4-CONH2-Ph 357 4-Cl-Ph 4-CONHMe-Ph 358 4-Cl-Ph 4-CONHPh-Ph 359 4-Cl-Ph4-NHCONH2-Ph 360 4-Cl-Ph 4-F-Ph 361 4-Cl-Ph 4-Cl-Ph 362 4-Cl-Ph 4-Br-Ph363 4-Cl-Ph 4-NO2-Ph 364 4-Cl-Ph 4-NH2-Ph 365 4-Cl-Ph 4-NHMe-Ph 3664-Cl-Ph 4-NMe2-Ph 367 4-Cl-Ph 4-NHCOCH3-Ph 368 4-Cl-Ph 4-SO2NH2-Ph 3694-Cl-Ph 4-SO2NHMe-Ph 370 4-Cl-Ph 4-CF3-Ph 371 4-Cl-Ph 4-OCH3-Ph 3724-Cl-Ph 4-OPh-Ph 373 4-Cl-Ph 4-OCF3-Ph 374 4-Cl-Ph 4-SCH3-Ph 375 4-Cl-Ph4-SOCH3-Ph 376 4-Cl-Ph 4-SO2CH3-Ph 377 4-Cl-Ph 4-OH-Ph 378 4-Cl-Ph4-CH2OH-Ph 379 4-Cl-Ph 4-CHOHCH3-Ph 380 4-Cl-Ph 4-COH(CH3)2-Ph 3814-Cl-Ph 4-CH3-Ph 382 4-Cl-Ph 4-C2H5-Ph 383 4-Cl-Ph 4-iPr-Ph 384 4-Cl-Ph4-tBu-Ph 385 4-Cl-Ph 4-Ph-Ph 386 4-Cl-Ph 4-CH2Ph-Ph 387 4-Cl-Ph4-CH2CO2Me-Ph 388 4-Cl-Ph 4-(1-piperidinyl)-Ph 389 4-Cl-Ph4-(1-pyrrolidinyl)-Ph 390 4-Cl-Ph 4-(2-imidazolyl)-Ph 391 4-Cl-Ph4-(1-imidazolyl)-Ph 392 4-Cl-Ph 4-(2-thiazolyl)-Ph 393 4-Cl-Ph4-(3-pyrazolyl)-Ph 394 4-Cl-Ph 4-(1-pyrazolyl)-Ph 395 4-Cl-Ph4-(1-tetrazolyl)-Ph 396 4-Cl-Ph 4-(5-tetrazolyl)-Ph 397 4-Cl-Ph4-(2-pyridyl)-Ph 398 4-Cl-Ph 4-(2-thienyl)-Ph 399 4-Cl-Ph4-(2-furanyl)-Ph 400 4-Cl-Ph 2-CN-Ph 401 4-Cl-Ph 2-COCH3-Ph 402 4-Cl-Ph2-CO2Me-Ph 403 4-Cl-Ph 2-CO2Et-Ph 404 4-Cl-Ph 2-CO2H-Ph 405 4-Cl-Ph2-CONH2-Ph 406 4-Cl-Ph 2-CONHMe-Ph 407 4-Cl-Ph 2-F-Ph 408 4-Cl-Ph2-Cl-Ph 409 4-Cl-Ph 2-Br-Ph 410 4-Cl-Ph 2-NO2-Ph 411 4-Cl-Ph 2-NH2-Ph412 4-Cl-Ph 2-NHMe-Ph 413 4-Cl-Ph 2-NMe2-Ph 414 4-Cl-Ph 2-NHCOCH3-Ph 4154-Cl-Ph 2-SO2NH2-Ph 416 4-Cl-Ph 2-SO2NHMe-Ph 417 4-Cl-Ph 2-CF3-Ph 4184-Cl-Ph 2-OCH3-Ph 419 4-Cl-Ph 2-OPh-Ph 420 4-Cl-Ph 2-OCF3-Ph 421 4-Cl-Ph2-SCH3-Ph 422 4-Cl-Ph 2-SOCH3 -Ph 423 4-Cl-Ph 2-SO2CH3-Ph 424 4-Cl-Ph2-OH-Ph 425 4-Cl-Ph 2-CH2OH-Ph 426 4-Cl-Ph 2-CHOHCH3-Ph 427 4-Cl-Ph2-COH(CH3)2-Ph 428 4-Cl-Ph 2-CHOHPh-Ph 429 4-Cl-Ph 2-CH3-Ph 430 4-Cl-Ph2-C2H5-Ph 431 4-Cl-Ph 2-iPr-Ph 432 4-Cl-Ph 2-tBu-Ph 433 4-Cl-Ph 2-Ph-Ph434 4-Cl-Ph 2-CH2Ph-Ph 435 4-Cl-Ph 2-CH2CO2Me-Ph 436 4-Cl-Ph2-(1-piperidinyl)-Ph 437 4-Cl-Ph 2-(1-pyrrolidinyl)-Ph 438 4-Cl-Ph2-(2-imidazolyl)-Ph 439 4-Cl-Ph 2-(1-imidazolyl)-Ph 440 4-Cl-Ph2-(2-thiazolyl)-Ph 441 4-Cl-Ph 2-(3-pyrazolyl)-Ph 442 4-Cl-Ph2-(1-pyrazolyl)-Ph 443 4-Cl-Ph 2-(1-tetrazolyl)-Ph 444 4-Cl-Ph2-(5-tetrazolyl)-Ph 445 4-Cl-Ph 2-(2-pyridyl)-Ph 446 4-Cl-Ph2-(2-thienyl)-Ph 447 4-Cl-Ph 2-(2-furanyl)-Ph 448 4-Cl-Ph 2,4-diF-Ph 4494-Cl-Ph 2,5-diF-Ph 450 4-Cl-Ph 2,6-diF-Ph 451 4-Cl-Ph 3,4-diF-Ph 4524-Cl-Ph 3,5-diF-Ph 453 4-Cl-Ph 2,4-diCl-Ph 454 4-Cl-Ph 2,5-diCl-Ph 4554-Cl-Ph 2,6-diCl-Ph 456 4-Cl-Ph 3,4-diCl-Ph 457 4-Cl-Ph 3,5-diCl-Ph 4584-Cl-Ph 3,4-diCF3-Ph 459 4-Cl-Ph 3,5-diCF3-Ph 460 4-Cl-Ph 5-Cl-2-MeO-Ph461 4-Cl-Ph 5-Cl-2-Me-Ph 462 4-Cl-Ph 2-F-S-Me-Ph 463 4-Cl-Ph2-F-5-NO2-Ph 464 4-Cl-Ph 3,4-OCH2O-Ph 465 4-Cl-Ph 3,4-OCH2CH2O-Ph 4664-Cl-Ph 2-MeO-4-Me-Ph 467 4-Cl-Ph 2-MeO-5-Me-Ph 468 4-Cl-Ph 1-naphthyl469 4-Cl-Ph 2-naphthyl 470 4-Cl-Ph 2-thienyl 471 4-Cl-Ph 3-thienyl 4724-Cl-Ph 2-furanyl 473 4-Cl-Ph 3-furanyl 474 4-Cl-Ph 2-pyridyl 4754-Cl-Ph 3-pyridyl 476 4-Cl-Ph 4-pyridyl 477 4-Cl-Ph 2-indolyl 4784-Cl-Ph 3-indolyl 479 4-Cl-Ph 5-indolyl 480 4-Cl-Ph 6-indolyl 4814-Cl-Ph 3-indazolyl 482 4-Cl-Ph 5-indazolyl 483 4-Cl-Ph 6-indazolyl 4844-Cl-Ph 2-imidazolyl 485 4-Cl-Ph 3-pyrazolyl 486 4-Cl-Ph 2-thiazolyl 4874-Cl-Ph 5-tetrazolyl 488 4-Cl-Ph 2-benzimidazolyl 489 4-Cl-Ph5-benzimidazolyl 490 4-Cl-Ph 2-benzothiazolyl 491 4-Cl-Ph5-benzothiazolyl 492 4-Cl-Ph 2-benzoxazolyl 493 4-Cl-Ph 5-benzoxazolyl494 2-Cl-Ph 3-CN-Ph 495 2-Cl-Ph 3-COCH3-Ph 496 2-Cl-Ph 3-CO2Me-Ph 4972-Cl-Ph 3-CO2Et-Ph 498 2-Cl-Ph 3-CO2H-Ph 499 2-Cl-Ph 3-CONH2-Ph 5002-Cl-Ph 3-F-Ph 501 2-Cl-Ph 3-Cl-Ph 502 2-Cl-Ph 3-NH2-Ph 503 2-Cl-Ph3-SO2NH2-Ph 504 2-Cl-Ph 3-CF3-Ph 505 2-Cl-Ph 3-OCH3-Ph 506 2-Cl-Ph3-OEt-Ph 507 2-Cl-Ph 3-OCF3-Ph 508 2-Cl-Ph 3-SO2CH3-Ph 509 2-Cl-Ph3-OH-Ph 510 2-Cl-Ph 3-CH3-Ph 511 2-Cl-Ph 3-C2H5-Ph 512 2-Cl-Ph 4-CN-Ph513 2-Cl-Ph 4-COCH3-Ph 514 2-Cl-Ph 4-CO2Me-Ph 515 2-Cl-Ph 4-CO2Et-Ph 5162-Cl-Ph 4-CO2H-Ph 517 2-Cl-Ph 4-CONH2-Ph 518 2-Cl-Ph 4-F-Ph 519 2-Cl-Ph4-Cl-Ph 520 2-Cl-Ph 4-NH2-Ph 521 2-Cl-Ph 4-SO2NH2-Ph 522 2-Cl-Ph4-CF3-Ph 523 2-Cl-Ph 4-OCH3-Ph 524 2-Cl-Ph 4-OEt-Ph 525 2-Cl-Ph4-OCF3-Ph 526 2-Cl-Ph 4-SO2CH3-Ph 527 2-Cl-Ph 4-OH-Ph 528 2-Cl-Ph4-CH3-Ph 529 2-Cl-Ph 4-C2H5-Ph 530 2-Cl-Ph 2,4-diF-Ph 531 2-Cl-Ph2,5-diF-Ph 532 2-Cl-Ph 3,4-diF-Ph 533 2-Cl-Ph 3,5-diF-Ph 534 2-Cl-Ph2,4-diCl-Ph 535 2-Cl-Ph 2,5-diCl-Ph 536 2-Cl-Ph 3,4-diCl-Ph 537 2-Cl-Ph3,5-diCl-Ph 538 2-Cl-Ph 3,4-OCH2O-Ph 539 2-Cl-Ph 3,4-OCH2CH2O-Ph 5402-Cl-Ph 2-thienyl 541 2-Cl-Ph 2-furanyl 542 2-Cl-Ph 2-pyridyl 5432-Cl-Ph 4-pyridyl 544 2-Cl-Ph 2-imidazolyl 545 2-Cl-Ph 3-pyrazolyl 5462-Cl-Ph 2-thiazolyl 547 2-Cl-Ph 5-tetrazolyl 548 2,4-diCl-Ph 3-CN-Ph 5492,4-diCl-Ph 3-COCH3-Ph 550 2,4-diCl-Ph 3-CO2Me-Ph 551 2,4-diCl-Ph3-CO2Et-Ph 552 2,4-diCl-Ph 3-CO2H-Ph 553 2,4-diCl-Ph 3-CONH2-Ph 5542,4-diCl-Ph 3-F-Ph 555 2,4-diCl-Ph 3-Cl-Ph 556 2,4-diCl-Ph 3-NH2-Ph 5572,4-diCl-Ph 3-SO2NH2-Ph 558 2,4-diCl-Ph 3-CF3-Ph 559 2,4-diCl-Ph3-OCH3-Ph 560 2,4-diCl-Ph 3-OEt-Ph 561 2,4-diCl-Ph 3-OCF3-Ph 5622,4-diCl-Ph 3-SO2CH3-Ph 563 2,4-diCl-Ph 3-OH-Ph 564 2,4-diCl-Ph 3-CH3-Ph565 2,4-diCl-Ph 3-C2H5-Ph 566 2,4-diCl-Ph 4-CN-Ph 567 2,4-diCl-Ph4-COCH3-Ph 568 2,4-diCl-Ph 4-CO2Me-Ph 569 2,4-diCl-Ph 4-CO2Et-Ph 5702,4-diCl-Ph 4-CO2H-Ph 571 2,4-diCl-Ph 4-CONH2-Ph 572 2,4-diCl-Ph 4-F-Ph573 2,4-diCl-Ph 4-Cl-Ph 574 2,4-diCl-Ph 4-NH2-Ph 575 2,4-diCl-Ph4-SO2NH2-Ph 576 2,4-diCl-Ph 4-CF3-Ph 577 2,4-diCl-Ph 4-OCH3-Ph 5782,4-diCl-Ph 4-OEt-Ph 579 2,4-diCl-Ph 4-OCF3-Ph 580 2,4-diCl-Ph4-SO2CH3-Ph 581 2,4-diCl-Ph 4-OH-Ph 582 2,4-diCl-Ph 4-CH3-Ph 5832,4-diCl-Ph 4-C2H5-Ph 584 2,4-diCl-Ph 2,4-diF-Ph 585 2,4-diCl-Ph2,5-diF-Ph 586 2,4-diCl-Ph 3,4-diF-Ph 587 2,4-diCl-Ph 3,5-diF-Ph 5882,4-diCl-Ph 2,4-diCl-Ph 589 2,4-diCl-Ph 2,5-diCl-Ph 590 2,4-diCl-Ph3,4-diCl-Ph 591 2,4-diCl-Ph 3,5-diCl-Ph 592 2,4-diCl-Ph 3,4-OCH2O-Ph 5932,4-diCl-Ph 3,4-OCH2CH2O-Ph 594 2,4-diCl-Ph 2-thienyl 595 2,4-diCl-Ph2-furanyl 596 2,4-diCl-Ph 2-pyridyl 597 2,4-diCl-Ph 4-pyridyl 5982,4-diCl-Ph 2-imidazolyl 599 2,4-diCl-Ph 3-pyrazolyl 600 2,4-diCl-Ph2-thiazolyl 601 2,4-diCl-Ph 5-tetrazolyl 602 3-OCH3-Ph 3-CN-Ph 6033-OCH3-Ph 3-COCH3-Ph 604 3-OCH3-Ph 3-CO2Me-Ph 605 3-OCH3-Ph 3-CO2Et-Ph606 3-OCH3-Ph 3-CO2H-Ph 607 3-OCH3-Ph 3-CONH2-Ph 608 3-OCH3-Ph 3-F-Ph609 3-OCH3-Ph 3-Cl-Ph 610 3-OCH3-Ph 3-NH2-Ph 611 3-OCH3-Ph 3-SO2NH2-Ph612 3-OCH3-Ph 3-CF3-Ph 613 3-OCH3-Ph 3-OCH3-Ph 614 3-OCH3-Ph 3-OEt-Ph615 3-OCH3-Ph 3-OCF3-Ph 616 3-OCH3-Ph 3-SO2CH3-Ph 617 3-OCH3-Ph 3-OH-Ph618 3-OCH3-Ph 3-CH3-Ph 619 3-OCH3-Ph 3-C2H5-Ph 620 3-OCH3-Ph 4-CN-Ph 6213-OCH3-Ph 4-COCH3-Ph 622 3-OCH3-Ph 4-CO2Me-Ph 623 3-OCH3-Ph 4-CO2Et-Ph624 3-OCH3-Ph 4-CO2H-Ph 625 3-OCH3-Ph 4-CONH2-Ph 626 3-OCH3-Ph 4-F-Ph627 3-OCH3-Ph 4-Cl-Ph 628 3-OCH3-Ph 4-NH2-Ph 629 3-OCH3-Ph 4-SO2NH2-Ph630 3-OCH3-Ph 4-CF3-Ph 631 3-OCH3-Ph 4-OCH3-Ph 632 3-OCH3-Ph 4-OEt-Ph633 3-OCH3-Ph 4-OCF3-Ph 634 3-OCH3-Ph 4-SO2CH3-Ph 635 3-OCH3-Ph 4-OH-Ph636 3-OCH3-Ph 4-CH3-Ph 637 3-OCH3-Ph 4-C2H5-Ph 638 3-OCH3-Ph 2,4-diF-Ph639 3-OCH3-Ph 2,5-diF-Ph 640 3-OCH3-Ph 3,4-diF-Ph 641 3-OCH3-Ph3,5-diF-Ph 642 3-OCH3-Ph 2,4-diCl-Ph 643 3-OCH3-Ph 2,5-diCl-Ph 6443-OCH3-Ph 3,4-diCl-Ph 645 3-OCH3-Ph 3,5-diCl-Ph 646 3-OCH3-Ph3,4-OCH2O-Ph 647 3-OCH3-Ph 3,4-OCH2CH2O-Ph 648 3-OCH3-Ph 2-thienyl 6493-OCH3-Ph 2-furanyl 650 3-OCH3-Ph 2-pyridyl 651 3-OCH3-Ph 4-pyridyl 6523-OCH3-Ph 2-imidazolyl 653 3-OCH3-Ph 3-pyrazolyl 654 3-OCH3-Ph2-thiazolyl 655 3-OCH3-Ph 5-tetrazolyl

TABLE 2 a

b

c

d

ENTRY R5 R3 1 6-F Ph 2 6-F 3-CN-Ph 3 6-F 3-COCH3-Ph 4 6-F 3-CO2Me-Ph 56-F 3-CO2Et-Ph 6 6-F 3-CO2H-Ph 7 6-F 3-CONH2-Ph 8 6-F 3-CONHMe-Ph 9 6-F3-F-Ph 10 6-F 3-Cl-Ph 11 6-F 3-Br-Ph 12 6-F 3-NO2-Ph 13 6-F 3-NH2-Ph 146-F 3-NHMe-Ph 15 6-F 3-NMe2-Ph 16 6-F 3-NHCOCH3-Ph 17 6-F 3-SO2NH2-Ph 186-F 3-SO2NHMe-Ph 19 6-F 3-CF3-Ph 20 6-F 3-OCH3-Ph 21 6-F 3-OPh-Ph 22 6-F3-OCF3-Ph 23 6-F 3-SCH3-Ph 24 6-F 3-SOCH3-Ph 25 6-F 3-SO2CH3-Ph 26 6-F3-OH-Ph 27 6-F 3-CH2OH-Ph 28 6-F 3-CHOHCH3-Ph 29 6-F 3-COH(CH3)2-Ph 306-F 3-CHOHPh-Ph 31 6-F 3-CH3-Ph 32 6-F 3-C2H5-Ph 33 6-F 3-iPr-Ph 34 6-F3-tBu-Ph 35 6-F 3-Ph-Ph 36 6-F 3-CH2Ph-Ph 37 6-F 3-CH2CO2Me-Ph 38 6-F3-(1-piperidinyl)-Ph 39 6-F 3-(1-pyrrolidinyl)-Ph 40 6-F3-(2-imidazolyl)-Ph 41 6-F 3-(1-imidazolyl)-Ph 42 6-F 3-(2-thiazolyl)-Ph43 6-F 3-(3-pyrazolyl)-Ph 44 6-F 3-(1-pyrazolyl)-Ph 45 6-F3-(1-tetrazolyl)-Ph 46 6-F 3-(5-tetrazolyl)-Ph 47 6-F 3-(2-pyridyl)-Ph48 6-F 3-(2-thienyl)-Ph 49 6-F 3-(2-furanyl)-Ph 50 6-F 4-CN-Ph 51 6-F4-COCH3-Ph 52 6-F 4-CO2Me-Ph 53 6-F 4-CO2Et-Ph 54 6-F 4-CO2H-Ph 55 6-F4-CONH2-Ph 56 6-F 4-CONHMe-Ph 57 6-F 4-CONHPh-Ph 58 6-F 4-NHCONH2-Ph 596-F 6-F 60 6-F 4-Cl-Ph 61 6-F 4-Br-Ph 62 6-F 4-NO2-Ph 63 6-F 4-NH2-Ph 646-F 4-NHMe-Ph 65 6-F 4-NMe2-Ph 66 6-F 4-NHCOCH3-Ph 67 6-F 4-SO2NH2-Ph 686-F 4-SO2NHMe-Ph 69 6-F 4-CF3-Ph 70 6-F 4-OCH3-Ph 71 6-F 4-OPh-Ph 72 6-F4-OCF3-Ph 73 6-F 4-SCH3-Ph 74 6-F 4-SOCH3-Ph 75 6-F 4-SO2CH3-Ph 76 6-F4-OH-Ph 77 6-F 4-CH2OH-Ph 78 6-F 4-CHOHCH3-Ph 79 6-F 4-COH(CH3)2-Ph 806-F 4-CH3-Ph 81 6-F 4-C2H5-Ph 82 6-F 4-iPr-Ph 83 6-F 4-tBu-Ph 84 6-F4-Ph-Ph 85 6-F 4-CH2Ph-Ph 86 6-F 4-CH2CO2Me-Ph 87 6-F4-(1-piperidinyl)-Ph 88 6-F 4-(1-pyrrolidinyl)-Ph 89 6-F4-(2-imidazolyl)-Ph 90 6-F 4-(1-imidazolyl)-Ph 91 6-F 4-(2-thiazolyl)-Ph92 6-F 4-(3-pyrazolyl)-Ph 93 6-F 4-(1-pyrazolyl)-Ph 94 6-F4-(1-tetrazolyl)-Ph 95 6-F 4-(5-tetrazolyl)-Ph 96 6-F 4-(2-pyridyl)-Ph97 6-F 4-(2-thienyl)-Ph 98 6-F 4-(2-furanyl)-Ph 99 6-F 2-CN-Ph 100 6-F2-COCH3-Ph 101 6-F 2-CO2Me-Ph 102 6-F 2-CO2Et-Ph 103 6-F 2-CO2H-Ph 1046-F 2-CONH2-Ph 105 6-F 2-CONHMe-Ph 106 6-F 2-F-Ph 107 6-F 2-Cl-Ph 1086-F 2-Br-Ph 109 6-F 2-NO2-Ph 110 6-F 2-NH2-Ph 111 6-F 2-NHMe-Ph 112 6-F2-NMe2-Ph 113 6-F 2-NHCOCH3-Ph 114 6-F 2-SO2NH2-Ph 115 6-F 2-SO2NHMe-Ph116 6-F 2-CF3-Ph 117 6-F 2-OCH3-Ph 118 6-F 2-OPh-Ph 119 6-F 2-OCF3-Ph120 6-F 2-SCH3-Ph 121 6-F 2-SOCH3-Ph 122 6-F 2-SO2CH3-Ph 123 6-F 2-OH-Ph124 6-F 2-CH2OH-Ph 125 6-F 2-CHOHCH3-Ph 126 6-F 2-COH(CH3)2-Ph 127 6-F2-CHOHPh-Ph 128 6-F 2-CH3-Ph 129 6-F 2-C2H5-Ph 130 6-F 2-iPr-Ph 131 6-F2-tBu-Ph 132 6-F 2-Ph-Ph 133 6-F 2-CH2Ph-Ph 134 6-F 2-CH2CO2Me-Ph 1356-F 2-(1-piperidmyl)-Ph 136 6-F 2-(1-pyrrolidinyl)-Ph 137 6-F2-(2-imidazolyl)-Ph 138 6-F 2-(1-imidazolyl)-Ph 139 6-F2-(2-thiazolyl)-Ph 140 6-F 2-(3-pyrazolyl)-Ph 141 6-F 2-(1-pyrazolyl)-Ph142 6-F 2-(1-tetrazolyl)-Ph 143 6-F 2-(5-tetrazolyl)-Ph 144 6-F2-(2-pyridyl)-Ph 145 6-F 2-(2-thienyl)-Ph 146 6-F 2-(2-faranyl)-Ph 1476-F 2,4-diF-Ph 148 6-F 2,5-diF-Ph 149 6-F 2,6-diF-Ph 150 6-F 3,4-diF-Ph151 6-F 3,5-diF-Ph 152 6-F 2,4-diCl-Ph 153 6-F 2,5-diCl-Ph 154 6-F2,6-diCl-Ph 155 6-F 3,4-diCl-Ph 156 6-F 3,5-diCl-Ph 157 6-F 3,4-diCF3-Ph158 6-F 3,5-diCF3-Ph 159 6-F 5-Cl-2-MeO-Ph 160 6-F 5-Cl-2-Me-Ph 161 6-F2-F-5-Me-Ph 162 6-F 2-F-5-NO2-Ph 163 6-F 3,4-OCH2O-Ph 164 6-F3,4-OCH2CH2O-Ph 165 6-F 2-MeO-4-Me-Ph 166 6-F 2-MeO-5-Me-Ph 167 6-F1-naphthyl 168 6-F 2-naphthyl 169 6-F 2-thienyl 170 6-F 3-thienyl 1716-F 2-furanyl 172 6-F 3-furanyl 173 6-F 2-pyridyl 174 6-F 3-pyridyl 1756-F 4-pyridyl 176 6-F 2-indolyl 177 6-F 3-indolyl 178 6-F 5-indolyl 1796-F 6-indolyl 180 6-F 3-mdazolyl 181 6-F 5-indazolyl 182 6-F 6-indazolyl183 6-F 2-imidazolyl 184 6-F 3-pyrazolyl 185 6-F 2-thiazolyl 186 6-F5-tetrazolyl 187 6-F 2-benzimidazolyl 188 6-F 5-benzimidazolyl 189 6-F2-benzothiazolyl 190 6-F 5-benzothiazolyl 191 6-F 2-benzoxazolyl 192 6-F5-benzoxazolyl 193 7-F 3-CN-Ph 194 7-F 3-COCH3-Ph 195 7-F 3-CO2Me-Ph 1967-F 3-CO2Et-Ph 197 7-F 3-CO2H-Ph 198 7-F 3-CONH2-Ph 199 7-F 3-F-Ph 2007-F 3-Cl-Ph 201 7-F 3-NH2-Ph 202 7-F 3-SO2NH2-Ph 203 7-F 3-CF3-Ph 2047-F 3-OCH3-Ph 205 7-F 3-OEt-Ph 206 7-F 3-OCF3-Ph 207 7-F 3-SO2CH3-Ph 2087-F 3-OH-Ph 209 7-F 3-CH3-Ph 210 7-F 3-C2H5-Ph 211 7-F 4-CN-Ph 212 7-F4-COCH3-Ph 213 7-F 4-CO2Me-Ph 214 7-F 4-CO2Et-Ph 215 7-F 4-CO2H-Ph 2167-F 4-CONH2-Ph 217 7-F 4-F-Ph 218 7-F 4-Cl-Ph 219 7-F 4-NH2-Ph 220 7-F4-SO2NH2-Ph 221 7-F 4-CF3-Ph 222 7-F 4-OCH3-Ph 223 7-F 4-OEt-Ph 224 7-F4-OCF3-Ph 225 7-F 4-SO2CH3-Ph 226 7-F 4-OH-Ph 227 7-F 4-CH3-Ph 228 7-F4-C2H5-Ph 229 7-F 2,4-diF-Ph 230 7-F 2,5-diF-Ph 231 7-F 3,4-diF-Ph 2327-F 3,5-diF-Ph 233 7-F 2,4-diCl-Ph 234 7-F 2,5-diCI-Ph 235 7-F3,4-diCl-Ph 236 7-F 3,5-diCl-Ph 237 7-F 3,4-OCH2O-Ph 238 7-F3,4-OCH2CH2O-Ph 239 7-F 2-thienyl 240 7-F 2-furanyl 241 7-F 2-pyridyl242 7-F 4-pyridyl 243 7-F 2-imidazolyl 244 7-F 3-pyrazolyl 245 7-F2-thiazolyl 246 7-F 5-tetrazolyl 247 7-F 1-adamantyl 248 6,7-diF 3-CN-Ph249 6,7-diF 3-COCH3-Ph 250 6,7-diF 3-CO2Me-Ph 251 6,7-diF 3-CO2Et-Ph 2526,7-diF 3-CO2H-Ph 253 6,7-diF 3-CONH2-Ph 254 6,7-diF 3-F-Ph 255 6,7-diF3-Cl-Ph 256 6,7-diF 3-NH2-Ph 257 6,7-diF 3-SO2NH2-Ph 258 6,7-diF3-CF3-Ph 259 6,7-diF 3-OCH3-Ph 260 6,7-diF 3-OEt-Ph 261 6,7-diF3-OCF3-Ph 262 6,7-diF 3-SO2CH3-Ph 263 6,7-diF 3-OH-Ph 264 6,7-diF3-CH3-Ph 265 6,7-diF 3-C2H5-Ph 266 6,7-diF 4-CN-Ph 267 6,7-diF4-COCH3-Ph 268 6,7-diF 4-CO2Me-Ph 269 6,7-diF 4-CO2Et-Ph 270 6,7-diF4-CO2H-Ph 271 6,7-diF 4-CONH2-Ph 272 6,7-diF 4-F-Ph 273 6,7-diF 4-Cl-Ph274 6,7-diF 4-NH2-Ph 275 6,7-diF 4-SO2NH2-Ph 276 6,7-diF 4-CF3-Ph 2776,7-diF 4-OCH3-Ph 278 6,7-diF 4-OEt-Ph 279 6,7-diF 4-OCF3-Ph 280 6,7-diF4-SO2CH3-Ph 281 6,7-diF 4-OH-Ph 282 6,7-diF 4-CH3-Ph 283 6,7-diF4-C2H5-Ph 284 6,7-diF 6,7-diF 285 6,7-diF 2,5-diF-Ph 286 6,7-diF3,4-diF-Ph 287 6,7-diF 3,5-diF-Ph 288 6,7-diF 2,4-diCl-Ph 289 6,7-diF2,5-diCl-Ph 290 6,7-diF 3,4-diCl-Ph 291 6,7-diF 3,5-diCl-Ph 292 6,7-diF3,4-OCH2O-Ph 293 6,7-diF 3,4-OCH2CH2O-Ph 294 6,7-diF 2-thienyl 2956,7-diF 2-furanyl 296 6,7-diF 2-pyridyl 297 6,7-diF 4-pyridyl 2986,7-diF 2-imidazolyl 299 6,7-diF 3-pyrazolyl 300 6,7-diF 2-thiazolyl 3016,7-diF 5-tetrazolyl 302 6-Cl Ph 303 6-Cl 3-CN-Ph 304 6-Cl 3-COCH3-Ph305 6-Cl 3-CO2Me-Ph 306 6-Cl 3-CO2Et-Ph 307 6-Cl 3-CO2H-Ph 308 6-Cl3-CONH2-Ph 309 6-Cl 3-CONHMe-Ph 310 6-Cl 3-F-Ph 311 6-Cl 3-Cl-Ph 3126-Cl 3-Br-Ph 313 6-Cl 3-NO2-Ph 314 6-Cl 3-NH2-Ph 315 6-Cl 3-NHMe-Ph 3166-Cl 3-NMe2-Ph 317 6-Cl 3-NHCOCH3-Ph 318 6-Cl 3-SO2NH2-Ph 319 6-Cl3-SO2NHMe-Ph 320 6-Cl 3-CF3-Ph 321 6-Cl 3-OCH3-Ph 322 6-Cl 3-OPh-Ph 3236-Cl 3-OCF3-Ph 324 6-Cl 3-SCH3-Ph 325 6-Cl 3-SOCH3-Ph 326 6-Cl3-SO2CH3-Ph 327 6-Cl 3-OH-Ph 328 6-Cl 3-CH2OH-Ph 329 6-Cl 3-CHOHCH3-Ph330 6-Cl 3-COH(CH3)2-Ph 331 6-Cl 3-CHOHPh-Ph 332 6-Cl 3-CH3-Ph 333 6-Cl3-C2H5-Ph 334 6-Cl 3-iPr-Ph 335 6-Cl 3-tBu-Ph 336 6-Cl 3-Ph-Ph 337 6-Cl3-CH2Ph-Ph 338 6-Cl 3-CH2CO2Me-Ph 339 6-Cl 3-(1-piperidmyl)-Ph 340 6-Cl3-(1-pyrrolidinyl)-Ph 341 6-Cl 3-(2-imidazolyl)-Ph 342 6-Cl3-(1-imidazolyl)-Ph 343 6-Cl 3-(2-thiazolyl)-Ph 344 6-Cl3-(3-pyrazolyl)-Ph 345 6-Cl 3-(1-pyrazolyl)-Ph 346 6-Cl3-(1-tetrazolyl)-Ph 347 6-Cl 3-(5-tetrazolyl)-Ph 348 6-Cl3-(2-pyridyl)-Ph 349 6-Cl 3-(2-thienyl)-Ph 350 6-Cl 3-(2-furanyl)-Ph 3516-Cl 4-CN-Ph 352 6-Cl 4-COCH3-Ph 353 6-Cl 4-CO2Me-Ph 354 6-Cl 4-CO2Et-Ph355 6-Cl 4-CO2H-Ph 356 6-Cl 4-CONH2-Ph 357 6-Cl 4-CONHMe-Ph 358 6-Cl4-CONHPh-Ph 359 6-Cl 4-NHCONH2-Ph 360 6-Cl 4-F-Ph 361 6-Cl 4-Cl-Ph 3626-Cl 4-Br-Ph 363 6-Cl 4-NO2-Ph 364 6-Cl 4-NH2-Ph 365 6-Cl 4-NHMe-Ph 3666-Cl 4-NMe2-Ph 367 6-Cl 4-NHCOCH3-Ph 368 6-Cl 4-SO2NH2-Ph 369 6-Cl4-SO2NHMe-Ph 370 6-Cl 4-CF3-Ph 371 6-Cl 4-OCH3-Ph 372 6-Cl 4-OPh-Ph 3736-Cl 4-OCF3-Ph 374 6-Cl 4-SCH3-Ph 375 6-Cl 4-SOCH3-Ph 376 6-Cl4-SO2CH3-Ph 377 6-Cl 4-OH-Ph 378 6-Cl 4-CH2OH-Ph 379 6-Cl 4-CHOHCH3-Ph380 6-Cl 4-COH(CH3)2-Ph 381 6-Cl 4-CH3-Ph 382 6-Cl 4-C2H5-Ph 383 6-Cl4-iPr-Ph 384 6-Cl 4-tBu-Ph 385 6-Cl 4-Ph-Ph 386 6-Cl 4-CH2Ph-Ph 387 6-Cl4-CH2CO2Me-Ph 388 6-Cl 4-(1-piperidinyl)-Ph 389 6-Cl4-(1-pyrrolidmyl)-Ph 390 6-Cl 4-(2-imidazolyl)-Ph 391 6-Cl4-(1-imidazolyl)-Ph 392 6-Cl 4-(2-thiazolyl)-Ph 393 6-Cl4-(3-pyrazolyl)-Ph 394 6-Cl 4-(1-pyrazolyl)-Ph 395 6-Cl4-(1-tetrazolyl)-Ph 396 6-Cl 4-(5-tetrazolyl)-Ph 397 6-Cl4-(2-pyridyl)-Ph 398 6-Cl 4-(2-thienyl)-Ph 399 6-Cl 4-(2-furanyl)-Ph 4006-Cl 2-CN-Ph 401 6-Cl 2-COCH3-Ph 402 6-Cl 2-CO2Me-Ph 403 6-Cl 2-CO2Et-Ph404 6-Cl 2-CO2H-Ph 405 6-Cl 2-CONH2-Ph 406 6-Cl 2-CONHMe-Ph 407 6-Cl2-F-Ph 408 6-Cl 2-Cl-Ph 409 6-Cl 2-Br-Ph 410 6-Cl 2-NO2-Ph 411 6-Cl2-NH2-Ph 412 6-Cl 2-NHMe-Ph 413 6-Cl 2-NMe2-Ph 414 6-Cl 2-NHCOCH3-Ph 4156-Cl 2-SO2NH2-Ph 416 6-Cl 2-SO2NHMe-Ph 417 6-Cl 2-CF3-Ph 418 6-Cl2-OCH3-Ph 419 6-Cl 2-OPh-Ph 420 6-Cl 2-OCF3-Ph 421 6-Cl 2-SCH3-Ph 4226-Cl 2-SOCH3-Ph 423 6-Cl 2-SO2CH3-Ph 424 6-Cl 2-OH-Ph 425 6-Cl2-CH2OH-Ph 426 6-Cl 2-CHOHCH3-Ph 427 6-Cl 2-COH(CH3)2-Ph 428 6-Cl2-CHOHPh-Ph 429 6-Cl 2-CH3-Ph 430 6-Cl 2-C2H5-Ph 431 6-Cl 2-iPr-Ph 4326-Cl 2-tBu-Ph 433 6-Cl 2-Ph-Ph 434 6-Cl 2-CH2Ph-Ph 435 6-Cl2-CH2CO2Me-Ph 436 6-Cl 2-(1-piperidinyl)-Ph 437 6-Cl2-(1-pyrrolidinyl)-Ph 438 6-Cl 2-(2-imidazolyl)-Ph 439 6-Cl2-(1-imidazolyl)-Ph 440 6-Cl 2-(2-thiazolyl)-Ph 441 6-Cl2-(3-pyrazolyl)-Ph 442 6-Cl 2-(1-pyrazolyl)-Ph 443 6-Cl2-(1-tetrazolyl)-Ph 444 6-Cl 2-(5-tetrazolyl)-Ph 445 6-Cl2-(2-pyridyl)-Ph 446 6-Cl 2-(2-thienyl)-Ph 447 6-Cl 2-(2-furanyl)-Ph 4486-Cl 6,7-diF 449 6-Cl 2,5-diF-Ph 450 6-Cl 2,6-diF-Ph 451 6-Cl 3,4-diF-Ph452 6-Cl 3,5-diF-Ph 453 6-Cl 2,4-diCl-Ph 454 6-Cl 2,5-diCl-Ph 455 6-Cl2,6-diCl-Ph 456 6-Cl 3,4-diCl-Ph 457 6-Cl 3,5-diCl-Ph 458 6-Cl3,4-diCF3-Ph 459 6-Cl 3,5-diCF3-Ph 460 6-Cl 5-Cl-2-MeO-Ph 461 6-Cl5-Cl-2-Me-Ph 462 6-Cl 2-F-5-Me-Ph 463 6-Cl 2-F-5-NO2-Ph 464 6-Cl3,4-OCH2O-Ph 465 6-Cl 3,4-OCH2CH2O-Ph 466 6-Cl 2-MeO-4-Me-Ph 467 6-Cl2-MeO-5-Me-Ph 468 6-Cl 1-naphthyl 469 6-Cl 2-naphthyl 470 6-Cl 2-thienyl471 6-Cl 3-thienyl 472 6-Cl 2-furanyl 473 6-Cl 3-furanyl 474 6-Cl2-pyridyl 475 6-Cl 3-pyridyl 476 6-Cl 4-pyridyl 477 6-Cl 2-indolyl 4786-Cl 3-indolyl 479 6-Cl 5-indolyl 480 6-Cl 6-indolyl 481 6-Cl3-indazolyl 482 6-Cl 5-indazolyl 483 6-Cl 6-indazolyl 484 6-Cl2-imidazolyl 485 6-Cl 3-pyrazolyl 486 6-Cl 2-thiazolyl 487 6-Cl5-tetrazolyl 488 6-Cl 2-benzimidazolyl 489 6-Cl 5-benzimidazolyl 4906-Cl 2-benzothiazolyl 491 6-Cl 5-benzothiazolyl 492 6-Cl 2-benzoxazolyl493 6-Cl 5-benzoxazolyl 494 7-Cl 3-CN-Ph 495 7-Cl 3-COCH3-Ph 496 7-Cl3-CO2Me-Ph 497 7-Cl 3-CO2Et-Ph 498 7-Cl 3-CO2H-Ph 499 7-Cl 3-CONH2-Ph500 7-Cl 3-F-Ph 501 7-Cl 3-Cl-Ph 502 7-Cl 3-NH2-Ph 503 7-Cl 3-SO2NH2-Ph504 7-Cl 3-CF3-Ph 505 7-Cl 3-OCH3-Ph 506 7-Cl 3-OEt-Ph 507 7-Cl3-OCF3-Ph 508 7-Cl 3-SO2CH3-Ph 509 7-Cl 3-OH-Ph 510 7-Cl 3-CH3-Ph 5117-Cl 3-C2H5-Ph 512 7-Cl 4-CN-Ph 513 7-Cl 4-COCH3-Ph 514 7-Cl 4-CO2Me-Ph515 7-Cl 4-CO2Et-Ph 516 7-Cl 4-CO2H-Ph 517 7-Cl 4-CONH2-Ph 518 7-Cl4-F-Ph 519 7-Cl 4-Cl-Ph 520 7-Cl 4-NH2-Ph 521 7-Cl 4-SO2NH2-Ph 522 7-Cl4-CF3-Ph 523 7-Cl 4-OCH3-Ph 524 7-Cl 4-OEt-Ph 525 7-Cl 4-OCF3-Ph 5267-Cl 4-SO2CH3-Ph 527 7-Cl 4-OH-Ph 528 7-Cl 4-CH3-Ph 529 7-Cl 4-C2H5-Ph530 7-Cl 6,7-diF 531 7-Cl 2,5-diF-Ph 532 7-Cl 3,4-diF-Ph 533 7-Cl3,5-diF-Ph 534 7-Cl 2,4-diCl-Ph 535 7-Cl 2,5-diCl-Ph 536 7-Cl3,4-diCl-Ph 537 7-Cl 3,5-diCl-Ph 538 7-Cl 3,4-OCH2O-Ph 539 7-Cl3,4-OCH2CH2O-Ph 540 7-Cl 2-thienyl 541 7-Cl 2-furanyl 542 7-Cl 2-pyridyl543 7-Cl 4-pyridyl 544 7-Cl 2-imidazolyl 545 7-Cl 3-pyrazolyl 546 7-Cl2-thiazolyl 547 7-Cl 5-tetrazolyl 548 6,7-diCl 3-CN-Ph 549 6,7-diCl3-COCH3-Ph 550 6,7-diCl 3-CO2Me-Ph 551 6,7-diCl 3-CO2Et-Ph 552 6,7-diCl3-CO2H-Ph 553 6,7-diCl 3-CONH2-Ph 554 6,7-diCl 3-F-Ph 555 6,7-diCl3-Cl-Ph 556 6,7-diCl 3-NH2-Ph 557 6,7-diCl 3-SO2NH2-Ph 558 6,7-diCl3-CF3-Ph 559 6,7-diCl 3-OCH3-Ph 560 6,7-diCl 3-OEt-Ph 561 6,7-diCl3-OCF3-Ph 562 6,7-diCl 3-SO2CH3-Ph 563 6,7-diCl 3-OH-Ph 564 6,7-diCl3-CH3-Ph 565 6,7-diCl 3-C2H5-Ph 566 6,7-diCl 4-CN-Ph 567 6,7-diCI4-COCH3-Ph 568 6,7-diCl 4-CO2Me-Ph 569 6,7-diCl 4-CO2Et-Ph 570 6,7-diCl4-CO2H-Ph 571 6,7-diCl 4-CONH2-Ph 572 6,7-diCl 4-F-Ph 573 6,7-diCl4-Cl-Ph 574 6,7-diCl 4-NH2-Ph 575 6,7-diCl 4-SO2NH2-Ph 576 6,7-diCl4-CF3-Ph 577 6,7-diCl 4-OCH3-Ph 578 6,7-diCl 4-OEt-Ph 579 6,7-diCl4-OCF3-Ph 580 6,7-diCl 4-SO2CH3-Ph 581 6,7-diCl 4-OH-Ph 582 6,7-diCl4-CH3-Ph 583 6,7-diCl 4-C2H5-Ph 584 6,7-diCl 6,7-diF 585 6,7-diCl2,5-diF-Ph 586 6,7-diCl 3,4-diF-Ph 587 6,7-diCl 3,5-diF-Ph 588 6,7-diCl2,4-diCl-Ph 589 6,7-diCl 2,5-diCl-Ph 590 6,7-diCl 3,4-diCl-Ph 5916,7-diCl 3,5-diCl-Ph 592 6,7-diCl 3,4-OCH2O-Ph 593 6,7-diCl3,4-OCH2CH2O-Ph 594 6,7-diCl 2-thienyl 595 6,7-diCl 2-furanyl 5966,7-diCl 2-pyridyl 597 6,7-diCl 4-pyridyl 598 6,7-diCl 2-imidazolyl 5996,7-diCl 3-pyrazolyl 600 6,7-diCl 2-thiazolyl 601 6,7-diCl 5-tetrazolyl

Utility

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR-2 and CCR-3ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 1137-1143(1997). Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-5 present, or a cellengineered to express a recombinant chemokine receptor, such as CHO orHEK-293. Finally, blood or tissue cells, for example human peripheralblood eosinophils, isolated using methods as described by Hansel et al.,J. Immunol. Methods, 145, 105-110 (1991), can be utilized in suchassays. In particular, the compound of the present invention haveactivity in binding to the CCR-3 receptor in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.A general binding protocol is described below.

CCR3-Receptor Binding Protocol

Millipore filter plates (#MABVN1250) are treated with 5 μg/ml protaminein phosphate buffered saline, pH 7.2, for ten minutes at roomtemperature. Plates are washed three times with phosphate bufferedsaline and incubated with phosphate buffered saline for thirty minutesat room temperature. For binding, 50 μl of binding buffer (0.5% bovineserum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI1640 media) with or without a test concentration of a compound presentat a known concentration is combined with 50 μl of 125-I labeled humaneotaxin (to give a final concentration of 150 pM radioligand) and 50 μlof cell suspension in binding buffer containing 5×10⁵ total cells. Cellsused for such binding assays can include cell lines transfected with agene expressing CCR3 such as that described by Daugherty et al. (1996),isolated human eosinophils such as described by Hansel et al. (1991) orthe AML14.3D10 cell line after differentiation with butyric acid asdescribed by Tiffany et al. (1998). The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and plates washedthree times with binding buffer with 0.5M NaCl added. The plastic skirtis removed from the plate, the plate allowed to air dry, the wells punchout and CPM counted. The percent inhibition of binding is calculatedusing the total count obtained in the absence of any competing compoundor chemokine ligand and the background binding determined by addition of100 nM eotaxin in place of the test compound.

The utility of the compounds in accordance with the present invention asinhibitors of the migration of eosinophils or cell lines expressing thechemokine receptors may be demonstrated by methodology known in the art,such as the chemotaxis assay disclosed by Bacon et al., Brit. J.Pharmacol., 95, 966-974 (1988). In particular, the compound of thepresent invention have activity in inhibition of the migration ofeosinophils in the aforementioned assays. As used herein, “activity” isintended to mean a compound demonstrating an IC50 of 10 μM or lower inconcentration when measured in the aforementioned assays. Such a resultis indicative of the intrinsic activity of the compounds as modulatorsof chemokine receptor activity. A human eosinophil chemotaxis assayprotocol is described below.

Human Eosinophil Chemotaxis Assay

Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobepolyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in placeare warmed in a 37° C. incubator prior to assay. Freshly isolated humaneosinophils, isolated according to a method such as that described byHansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serumalbumin at 1×10⁶ cells/ml and warmed in a 37° C. incubator prior toassay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovineserum albumin is warmed in a 37° C. incubator prior to assay. Theeosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or withouta dilution of a test compound that is at two fold the desired finalconcentration. These mixtures are warmed in a 37° C. incubator prior toassay. The filter is separated from the prewarmed Neuroprobe chemotaxischamber and the eotaxin/compound mixture is placed into a PolyfiltronicsMPC 96 well plate that has been placed in the bottom part of the NeuroProbe chemotaxis chamber. The approximate volume is 370 microliters andthere should be a positive meniscus after dispensing. The filter isreplaced above the 96 well plate, the rubber gasket is attached to thebottom of the upper chamber, and the chamber assembled. A 200 μl volumeof the cell suspension/compound mixture is added to the appropriatewells of the upper chamber. The upper chamber is covered with a platesealer, and the assembled unit placed in a 37° C. incubator for 45minutes.

After incubation, the plate sealer is removed and all remaining cellsuspension is aspirated off. The chamber is disassembled and, whileholding the filter by the sides at a 90-degree angle, unmigrated cellsare washed away using a gentle stream of phosphate buffered salinedispensed from a squirt bottle and then the filter wiped with a rubbertipped squeegee. The filter is allowed to completely dry and immersedcompletely in Wright Giemsa stain for 30-45 seconds. The filter isrinsed with distilled water for 7 minutes, rinsed once with waterbriefly, and allowed to dry. Migrated cells are enumerated bymicroscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited. Forexample, eosinophilic infiltration to inflammatory sites (e.g., inasthma or allergic rhinitis) can be inhibited according to the presentmethod. In particular, the compound of the following examples hasactivity in blocking the migration of cells expressing the CCR-3receptor using the appropriate chemokines in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 μM or lower in concentration when measured in theaforementioned assays. Such a result is also indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) integrin antagonists such as those for selectins,ICAMs and VLA-4; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(H1—histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-W); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like.

Similar diluents can be used to make compressed tablets. Both tabletsand capsules can be manufactured as sustained release products toprovide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1. A compound of formula (I):A-E-NR¹-G  (I) or stereoisomers or pharmaceutically acceptable saltsthereof, wherein: A is selected from

E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),

ring D is selected from a C₃₋₆ carbocyclic residue and a 5 or 6 memberedheterocycle; G is selected from —C(O)R³, —C(O)NR²R³, —C(O)OR³,—SO₂NR²R³, —SO₂R³, —C(═S)NR²R³, C(═NR^(1a))NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, C(═C(CN)₂)NR²R³,

W, at each occurrence, is independently selected from C or N, providedat least two of W are C; X¹ and X² are independently selected from C andN; Z¹ is selected from C and N; Z² is selected from NR^(1′), O, S and C;R¹, R^(1′) and R² are independently selected from H, C₁₋₈ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(a); R^(1a) is independentlyselected from H, C₁₋₆ alkyl, —OH, —CN, —NO₂, (CH₂)_(r)C₃₋₆ cycloalkyl,and a (CH₂)_(r)C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(a);R^(a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CHR′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃,NO₂, CN, (CHR′)_(r)NR^(b)R^(b), (CHR′)_(r)OH, (CHR′)_(r)OR^(c),(CHR′)_(r)SH, (CHR′)_(r)SR^(c), (CHR′)_(r)C(O)R^(b),(CHR′)_(r)C(O)NR^(b)R^(b), (CHR′)_(r)NR^(b)C(O)Rb, (CHR′)_(r)C(O)OR^(b),(CHR′)_(r)OC(O)R^(c), (CHR′)_(r)CH(═NR^(b))NR^(b)R^(b),(CHR′)_(r)NHC(═NR^(b))NR^(b)R^(b), (CHR′)_(r)S(O)_(p)R^(c),(CHR′)_(r)S(O)₂NR^(b)R^(b), (CHR′)_(r)NR^(b)S(O)₂R^(c), and(CHR′)_(r)phenyl; R^(b), at each occurrence, is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(c), at each occurrence, isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; alternatively, R¹and R² join to form a 5, 6, or 7-membered ring substituted with 0-3R^(a); R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R¹⁵ and a (CR^(3′)R^(3″))_(r)-5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R¹⁵; R^(3′) and R^(3″), at each occurrence, areselected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R⁴ isabsent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a′), (CH₂)_(q)C(O)OR^(4a), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c); R^(4a) and R^(4a′), ateach occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R^(4b), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, andphenyl; R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a′), and (CH₂)_(r)phenyl; R⁷, is selected from H,C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH, (CHR′)_(q)SH,(CHR′)_(q)OR^(7d), (CHR′)_(q)SR^(7d), (CH₂CHR′)_(q)NR^(7a)R^(7a′),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(7b), (CHR′)_(r)C(O)NR^(7a)R^(7a′),(CHR′)_(q)NR^(7a)C(O)R^(7b), (CHR′)_(q)NR^(7a)C(O)H,(CHR′)_(r)C(O)OR^(7a), (CHR′)_(q)OC(O)R^(7b), (CHR′)_(q)S(O)_(p)R^(7b),(CHR′)_(q)S(O)₂NR^(7a)R^(7a′), (CHR′)_(q)NR^(7a)S(O)₂R^(7b),(CHR′)_(q)NHC(O)NR^(7a)R^(7a′), (CHR′)_(q)NHC(O)OR^(7a),(CHR′)_(q)OC(O)NR^(7a)R^(7a′), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(7c); R^(7a) and R^(7a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(7e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(7e); R^(7c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN,(CH₂)_(r)NR^(7f)R^(7f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(7b),(CH₂)_(r)C(O)NR^(7f)R^(7f), (CH₂)_(r)NR^(7f)C(O)R^(7b),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(7b),(CH₂)_(r)C(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)_(p)R^(7b),(CH₂)_(r)NHC(═NR^(7f))NR^(7f)R^(7f), (CH₂)_(r)S(O)₂NR^(7f)R^(7f),(CH₂)_(r)NR^(7f)S(O)₂R^(7b), and (CH₂)_(r)phenyl substituted with 0-3R^(7e); R^(7d), at each occurrence, is selected from methyl, CF₃, C₂₋₆alkyl substituted with 0-3 R^(7e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c); R^(7e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8a); R^(8a), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; alternatively, R⁷ and R⁸join to form C₃₋₇ cycloalkyl, ═NR^(8b), or ═O; R^(8b) is selected fromH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, and (CH₂)_(r)-phenyl; R⁹, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I,NO₂, CN, (CHR′)_(r)OH, (CHR′)_(r)SH, (CHR′)_(r)OR^(9d),(CHR′)_(r)SR^(9d), (CHR′)_(r)NR^(9a)R^(9a′), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)R^(9b), (CHR′)_(r)C(O)NR^(9a)R^(9a′),(CHR′)_(r)NR^(9a)C(O)R^(9b), (CHR′)_(r)NR^(9a)C(O)H,(CHR′)_(r)NR^(9a)C(O)NR^(9a)R^(9a), (CHR′)_(r)C(O)OR^(9a),(CHR′)_(r)OC(O)R^(9b), (CHR′)_(r)S(O)_(p)R^(9b),(CHR′)_(r)S(O)₂NR^(9a)R^(9a′), (CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆haloalkyl, a (CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(9c), and a (CHR′)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(9c);R^(9a) and R^(9a′), at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(9e); R^(9b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(9e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(9e); R^(9c)c, at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(9f)R^(9f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9f)R^(9f),(CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(9b), (CH₂)_(r)C(═NR^(9f))NR^(9f)R^(9f),(CH₂)_(r)S(O)_(p)R^(9b), (CH₂)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),(CH₂)_(r)S(O)₂NR^(9f)R^(9f), (CH₂)_(r)NR^(9f)S(O)₂R^(9b), and(CH₂)_(r)phenyl substituted with 0-3 R^(9e); R^(9d), at each occurrence,is selected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(9e),C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₁₀ carbocyclic residue substituted with0-3 R^(9c), and a 5-6 membered heterocyclic system containing 1-4heteroatoms selected from the group consisting of N, O, and Ssubstituted with 0-3 R^(9c); R^(9e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;R^(9f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁰, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, NO₂, CN, (CH₂)_(r)OH, (CH₂)_(r)OR^(10d),(CH₂)_(r)SR^(10d), (CH₂)_(r)NR^(10a)R^(10a′), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a′),(CH₂)_(r)NR^(10a)C(O)R^(10a), (CH₂)_(r)NR^(10a)C(O)H,(CH₂)_(r)C(O)OR^(10a), (CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R_(10a′), (CH₂)_(r)NR^(10a)S(O)₂R^(10b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(10c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(10c);R^(10a) and R^(10a′), at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(10e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(10f)R_(10f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10f)R^(10f),(CH₂)_(r)NR^(10f)C(O)R^(10a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(10b), (CH₂)_(r)C(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CH₂)_(r)S(O)₂NR^(10f)R^(10f), (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e); R^(10d), at eachoccurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(10e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(10c), and a 5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from the group consisting of N, O,and S substituted with 0-3 R^(10c); R^(10e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and(CH₂)_(r)phenyl; R^(10f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; alternatively, R⁹ and R¹⁰ join to form C₃₋₇cycloalkyl, 5-6-membered cyclic ketal, or ═O; with the proviso that whenR¹⁰ is —OH, R⁹ is not halogen, cyano, or bonded to the carbon to whichit is attached through a heteroatom; R¹¹, is selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH,(CH₂)_(q)OR^(11d), (CH₂)_(q)SR^(11d), (CH₂)_(q)NR^(11a)R^(11a′),(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11a)R^(11a′),(CH₂)_(q)NR^(11a)C(O)R^(11b), (CH₂)_(q)NR^(11a)C(O)NR^(11a)R^(11a),(CH₂)_(r)C(O)OR^(11a), (CH₂)_(q)OC(O)R^(11b), (CH₂)_(q)S(O)_(p)R^(11b),(CH₂)_(q)S(O)₂NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)S(O)₂R^(11b), C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(11c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11c);R^(11a) and R^(11a′), at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11c), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I,F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11f)R^(11f), (CH₂)_(r)OH,(CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(11b), (CH₂)_(r)C(O)NR^(11f)R^(11f),(CH₂)_(r)NR^(11f)C(O)R^(11a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(11b), (CH₂)_(r)C(═NR^(11f))NR^(11f)R^(11f),(CH₂)_(r)NHC(═NR^(11f))NR^(11f)R^(11f), (CH₂)_(r)S(O)_(p)R^(11b),(CH₂)_(r)S(O)₂NR^(11f)R^(11f), (CH₂)_(r)NR^(11f)S(O)₂R^(11b), and(CH₂)_(r)phenyl substituted with 0-3 R^(11e); R^(11d), at eachoccurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with0-3 R^(11e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(11c); R^(11e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² isselected from H, C₁₋₆ alkyl, (CH₂)_(q)OH, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(t)phenyl substituted with 0-3 R^(12a); R^(12a), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and(CH₂)_(r)phenyl; alternatively, R¹¹ and R¹² join to form C₃₋₇cycloalkyl; R¹⁴ is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, C(O)NR^(14a)R^(14a′), C(O)R^(14b), C(O)OC₁₋₄alkyl, (CH₂)_(r)S(O)_(p)R^(14b), (CH₂)_(r)phenyl substituted with 0-3R^(14c), OR^(14a), NR^(14a)R^(14a′), ═O, and NR^(14a)C(O)R^(14a′);R^(14a) and R^(14a′), at each occurrence, are selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with0-3 R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(14c); R^(14b), at each occurrence, is selected from C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(14c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(14c);and R^(14c), at each occurrence, is selected from C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(w)phenyl; R¹⁵, at each occurrence, isselected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂,CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,(CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a′),(CHR′)_(r)NHC(═NR^(15f))NR^(15a)R^(15a′),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(15e); R^(15a) andR^(15a′), at each occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈alkenyl, C₃₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(15e); R^(15b), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); R^(15d), at each occurrence, is selected from C₃₋₈alkenyl, C₃₋₈ alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3R^(15e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(15e), and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e);R^(15e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl; R^(15f), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a′), (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a′),(CHR′)_(r)NHC(═NR^(16f))NR^(16a)R^(16a′),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e);R^(16d), at each occurrence, is selected from C₃₋₈ alkenyl, C₃₋₈alkynyl, methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(16e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(16e); R^(16e), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; R^(16f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, andphenyl; R¹⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CHR′)_(r)OH, (CHR′)_(r)SH, (CHR′)_(r)OR^(17d), (CHR′)_(r)SR^(17d),(CHR′)_(r)NR^(17a)R^(17a′), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)R^(17b),(CHR′)_(r)C(O)NR^(17a)R^(17a′), (CHR′)_(r)NR^(17a)C(O)R^(17b),(CHR′)_(r)NR^(17a)C(O)H, (CHR′)_(r)C(O)OR^(17a), (CHR′)_(r)OC(O)R^(17b),(CHR′)_(r)S(O)_(p)R^(17b), (CHR′)_(r)S(O)₂NR^(17a)R^(17a′),(CHR′)_(r)NR^(17a)S(O)₂R^(17b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(17c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(17c); R^(17a) and R^(17a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(17e), anda (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(17e); R^(17b), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(17e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(17e);R^(17c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(17f)R^(17f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(17b),(CH₂)_(r)C(O)NR^(17f)R^(17f), (CH₂)_(r)NR^(17f)C(O)R^(17a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(17b),(CH₂)_(r)C(═NR^(17f))NR^(17f)R^(17f), (CH₂)_(r)S(O)_(p)R^(17b),(CH₂)_(r)NHC(═NR^(17f))NR^(17f)R^(17f), (CH₂)_(r)S(O)₂NR^(17f)R^(17f),(CH₂)_(r)NR^(17f)S(O)₂R^(17b), and (CH₂)_(r)phenyl substituted with 0-3R^(17e); R^(17d), at each occurrence, is selected from methyl, CF₃, C₁₋₆alkyl substituted with 0-3 R^(17e), C₃₋₆ alkenyl, C₃₋₆ alkynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(17c); R^(17e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(17f)R^(17f), and(CH₂)_(r)phenyl; R^(17f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹⁸, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH, (CHR′)_(q)SH, (CHR′)_(q)OR^(18d),(CHR′)_(q)SR^(18d), (CHR′)_(q)NR^(18a)R^(18a′), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)R^(18b), (CHR′)_(r)C(O)NR^(18a)R^(18a′),(CHR′)_(q)NR^(18a)C(O)R^(18b), (CHR′)_(q)NR^(18a)C(O)H,(CHR′)_(r)C(O)OR^(18a), (CHR′)_(q)OC(O)R^(18b),(CHR′)_(q)S(O)_(p)R^(18b), (CHR′)_(q)S(O)₂NR^(18a)R^(18a′),(CHR′)_(q)NR^(18a)S(O)₂R^(18b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(18c), and a (CHR′)_(r)5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(18c); R^(18a) and R^(18a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(18e), anda (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(18e); R^(18b), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(18e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(18e);R^(18c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(18f)R^(18f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(18b),(CH₂)_(r)C(O)NR^(18f)R^(18f), (CH₂)_(r)NR^(18f)C(O)R^(18b),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(18b),(CH₂)_(r)C(═NR^(18f))NR^(18f)R^(18f), (CH₂)_(r)S(O)_(p)R^(18b),(CH₂)_(r)NHC(═NR^(18f))NR^(18f)R^(18f), (CH₂)_(r)S(O)₂NR^(18f)R^(18f),(CH₂)_(r)NR^(18f)S(O)₂R^(18b), and (CH₂)_(r)phenyl substituted with 0-3R^(18e); R^(18d), at each occurrence, is selected from methyl, CF₃, C₁₋₆alkyl substituted with 0-3 R^(18e), C₃₋₆ alkenyl, C₃₋₆ alynyl, and aC₃₋₁₀ carbocyclic residue substituted with 0-3 R^(18c); R^(18e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(18f)R^(18f), and(CH₂)_(r)phenyl; R^(18f), at each occurrence, is selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; a is selected from 0 and 1; b is selectedfrom 0 and 1, wherein if a=0, then b=1; c is selected from 0, 1, and 2;d is selected from 0, 1, and 2, wherein c+d equals 1 or 2; provided thatif b=1, c=1, and d=1 then E cannot be—(CR⁷R⁸)—(CR⁹CR¹⁰)_(v)—(CR¹¹CR¹²)—; e is selected from 0 and 1; f isselected from 0 and 1, wherein e+f equals 1 or 2; g is selected from 0,1, 2 and 3; h is selected from 0 and 1; i is selected from 1, 2, 3, 4,and 5; j is selected from 0, 1, 2, 3, 4, and 5; k is selected from 0, 1,and 2; l is selected from 0, 1, 2 and 3, wherein l+h equals 2 or 3; v,at each occurrence, is independently selected from 0, 1, and 2; t, ateach occurrence, is selected from 1 and 2; w, at each occurrence, isselected from 0 and 1; r, at each occurrence, is selected from 0, 1, 2,3, 4, and 5; s, at each occurrence, is selected from 0, 1, 2, 3, 4, and5; q, at each occurrence, is selected from 1, 2, 3, 4, and 5; and p, ateach occurrence, is selected from 1 and
 2. 2. The compound according toclaim 1, wherein: R⁴ is absent or, taken with the nitrogen to which itis attached to form an N-oxide; R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, (CHR′)_(q)OH, (CHR′)_(q)OR^(7d),(CHR′)_(q)NR^(7a)R^(7a′), (CHR′)_(r)C(O)R^(7b),(CHR′)_(r)C(O)NR^(7a)R^(7a′), (CHR′)_(q)NR^(7a)C(O)R^(7b),(CHR′)_(q)NR^(7a)C(O)H, (CHR′)_(q)S(O)₂NR^(7a)R^(7a′),(CHR′)_(q)NR^(7a)S(O)₂R^(7b), (CHR′)_(q)NHC(O)NHR^(7a),(CHR′)_(q)NHC(O)OR^(7a), (CHR′)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a(CHR′)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7c), and a(CHR′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(7c); alternatively,R⁷ and R⁸ join to form C₃₋₇ cycloalkyl, ═NR^(8b), or ═O; R⁹, is selectedfrom H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CHR′)_(r)OH,(CHR′)_(r)OR^(9d), (CHR′)_(r)NR^(9a)R^(9a′), (CHR′)_(r)C(O)R^(9b),(CHR′)_(r)C(O)NR^(9a)R^(9a′), (CHR′)_(r)NR^(9a)C(O)R^(9b),(CHR′)_(r)NR^(9a)C(O)H, (CHR′)_(r)NR^(9a)C(O)NHR^(9a),(CHR′)_(r)NR^(9a)S(O)₂R^(9b), C₁₋₆ haloalkyl, a (CHR′)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9c), and a (CHR′)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9c); R¹⁰, is selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl; R¹¹, is selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)OR^(11d),(CH₂)_(q)NR^(11a)R^(11a′), (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11a)R^(11a′), (CH₂)_(q)NR^(11a)C(O)R^(11a),(CH₂)_(q)NR^(11a)C(O)NHR^(11a), (CH₂)_(q)NHC(O)NHR^(7a),(CH₂)_(q)NHC(O)OR^(7a), (CH₂)_(q)OC(O)NHR^(7a), C₁₋₆ haloalkyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(11c), and a(CH₂′)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11c).
 3. The compoundof claim 2, wherein: E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²),


4. The compound according to claim 3, wherein: G is selected from—C(O)R³, —C(O)NR²R³, —C(O)OR³, —SO₂NR²R³, —SO₂R³, —C(═S)NR²R³,C(═NR^(1a))NR²R³, C(═CHCN)NR²R³, C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³. 5.The compound according to claim 4, wherein: R¹⁷ is selected from H; R¹⁸is selected from H; j is selected from 0, 1, and 2; i is selected from 1and 2; s is selected from 0, 1, and 2; and g is selected from 0, 1, and2.
 6. The compound of claim 5, wherein: R¹ is selected from H; R² isselected from H; and G is selected from —C(O)NR²R³, C(═CHCN)NR²R³,C(═CHNO₂)NR²R³, and C(═C(CN)₂)NR²R³.
 7. The compound according to claim6, wherein: E is selected from —(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).
 8. Thecompound according to claim 7, wherein: R⁷ is selected from H; R⁸ isselected from H; and R¹² is selected from H.
 9. The compound of claim 8,wherein: R¹⁶, at each occurrence, is selected from methyl, ethyl,propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a′), (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 10. The compound of claim 9,wherein: R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R¹⁵ and a (CR^(3′)CR^(3″))_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, subtituted with 0-3 R¹⁵; R^(3′) and R^(3″), at eachoccurrence, are selected from H; R¹⁵, at each occurrence, is selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, and OH.
 11. The compound of claim 6,wherein: E is


12. The compound of claim 11, wherein: E is

ring D is selected from a C₃₋₆ carbocyclic residue; R⁷ is selected fromH; and R⁸ is selected from H.
 13. The compound of claim 12, wherein:R¹⁶, at each occurrence, is selected from methyl, ethyl, propyl,iso-propyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, F, CN, (CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)C(O)NR^(16a)R^(16a′), (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 14. The compound of claim 13,wherein: R³ is selected from a (CR^(3′)R^(3″))_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R¹⁵ and a (CR^(3′)CR^(3″))_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, subtituted with 0-3 R¹⁵; R^(3′) and R^(3″), at eachoccurrence, are selected from H; R¹⁵, at each occurrence, is selectedfrom C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR¹⁵S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 15. The compound of claim3, wherein: G is selected from


16. The compound of claim 15, wherein: R¹ is selected from H; both X¹and X² cannot be C; and Z² is selected from NR^(1′), O, and S.
 17. Thecompound of claim 16, wherein: R¹⁷ is selected from H; R¹⁸ is selectedfrom H; j is selected from 0, 1, and 2; i is selected from 1 and 2; s isselected from 0, 1, and 2; and g is selected from 0, 1, and
 2. 18. Thecompound of claim 17, wherein: E is selected from—(CR⁷R⁸)—(CR⁹R¹⁰)_(v)—(CR¹¹R¹²).
 19. The compound of claim 18, wherein:R⁷ is selected from H; R⁸ is selected from H; and R¹² is selected fromH.
 20. The compound of claim 19, wherein: R¹⁶, at each occurrence, isselected from methyl, ethyl, propyl, iso-propyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,I, CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H;and r is selected from 0, 1, and
 2. 21. The compound of claim 20,wherein: R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′),(CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d),(CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b)b, C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, I, CN, (CF₂)_(r)CF₃, and OH.
 22. The compound of claim17, wherein: E is


23. The compound of claim 22, wherein: E is

ring D is selected from a C₃₋₆ carbocyclic residue; R⁷ is selected fromH; R⁸ is selected from H.
 24. The compound of claim 23, wherein: R¹⁶, ateach occurrence, is selected from methyl, ethyl, propyl, iso-propyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, F, CN,(CHR′)_(r)NR^(16a)R^(16a′), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d),(CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a′),(CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, and(CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a) and R^(16a′), ateach occurrence, are selected from H, methyl, ethyl, and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(16e);R^(16e), at each occurrence, is selected from methyl, ethyl, Cl, F, Br,CN, CF₃, and OCH₃; R^(16f), at each occurrence, is selected from H; andr is selected from 0, 1, and
 2. 25. The compound of claim 24, wherein:R¹⁵, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, F, CN, (CHR′)_(r)NR^(15a)R^(15a′), (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)C(O)NR^(15a)R^(15a′), (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b),(CHR′)_(r)NR^(15f)C(O)NR^(15a)R^(15a′),(CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a′),(CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, isselected from H, and C₁₋₆ alkyl; R^(15a) and R^(15a′), at eachoccurrence, are selected from H, C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-2 heteroatoms selected from N,O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, isselected from C₁₋₆ alkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-2 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(15e); and R^(15e), at each occurrence, is selected from C₁₋₆alkyl, Cl, F, Br, CN, (CF₂)_(r)CF₃, and OH.
 26. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 1. 27. A methodfor modulation of chemokine receptor activity comprising administeringto a patient in need thereof a therapeutically effective amount of thecompounds of claim
 1. 28. A method for treating or preventinginflammatory diseases, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 29.A method for treating or preventing asthma, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of claim 1.